LC Sciences Whole Exome Sequencing Report



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SalespersonKyle Navel
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1. Introduction


Whole Exome Sequencing (WES) is an efficient strategy to selectively sequence the coding regions (exons) of a genome, typically human, to discover rare or common variants associated with a disorder or phenotype. By focusing sequence production on exons, which represents ~2.5% of the human genome, many more individuals can be examined at significantly reduced cost and time compared to sequencing their entire genomes. The most common methods rely on hybridization by oligonucleotide probes to 'capture' targeted DNA fragments, thereby enriching for exonic sequences. Targeted exonic sequences include well-established annotated coding and non-coding exons. Regions not within close proximity, on the order of 125-bases, of the targeted regions are not sequenced. Therefore, variants within introns, promoters or inter-genic regions are generally not detected.



The goal of this approach is to identify genetic variants that alter protein sequences, and to do this at a much lower cost than whole-genome sequencing. Since these variants can be responsible for both Mendelian and common polygenic diseases, such as Alzheimer's disease, whole exome sequencing has been applied both in academic research and as a clinical diagnostic.



2. Materials and Methods


2.1 DNA extraction and whole exome sequencing


Total DNA was isolated from whole blood collected in tubes with EDTA or tissue samples by using a standard DNA extraction protocol. The quantity of DNA was measured by reading A260/280 ratios by spectrophotometer. When A260/280 ratios located range 1.8 to 2.0, DNA was available. Then fragmented DNA samples by using sonication were subjected to library construction. Exome capture was performed using SureSelect Human All Exon V6 Kit (Agilent Technologies) following the vendor's recommended protocol and sequencing was performed using the Illumina Hiseq X Ten at LC Sciences for a 150-bp paired-end run.



Workflow of exome capture


2.2 Bioinformatics analysis


Sequence and primary analysis

We sequenced generating a total of (____) million paired-end reads of 150bp length. This yielded (_____)G of sequence, representing approximately (______) times the size of the human all exome (50Mb).Prior to alignment, the low quality reads (1, reads containing sequencing adaptors; 2, nucleotide with q quality score lower than 20) were removed. After that, a total of (_____)G bp of cleaned, paired-end reads were produced. The raw sequence data have been submitted to the NCBI Short Read Archive with accession number (_____).


Alignment and duplicate marking

For the alignment step, BWA is utilized to perform reference genome alignment with the reads contained in paired FASTQ files. And as first post-alignment processing step, Picard tools is utilized to identified and mark duplicate reads from BAM file.


Local realignment around INDELs

In the second post-alignment processing step, local read realignment is performed to correct for potential alignment errors around indels. Mapping of reads around the edges of indels often results in misaligned bases creating false positive SNP calls. Local realignment uses these mismatching bases to determine if a site should be realigned, and applies a computationally intensive algorithm to determine the most consistent placement of the reads with respect to the indel and remove misalignment artifacts.


Base quality score recalibration

Each base of each read has an associated quality score, corresponding to the probability of a sequencing error. Due to the Systematic biases, the reported quality scores are known to be inaccurate and as such must be recalibrated prior to genotyping. After recalibration, the recalibrated quality score in the output BAM will more closely correspond to the probability of a sequencing error.


Variant calling

Variant calls can be generated with GATK HaplotypeCaller or UnifiedGenotyper, which Examine the evidence for variation from reference via Bayesian inference.


Variant recalibration

A Gaussian mixture model is fit to assigning accurate confidence score to each putative mutation call and evaluating new potential variants.


Variant function annotation

Biological functional annotation is a crucial step in finding the links between genetic variation and disease. SnpEff is utilized to add biological information to a set of variants.




Bioinformatics pipeline for whole exome sequencing



3. Project information


3.1 Sample information


Species name: Human

Latin name: Homo sapiens

Specimens: tissue/whole blood


3.2 Disease information


Disease name: Infantile autism

Disease type: Complex disease

Maps: NA


3.3 Database


Dababase Web links Version/date
Genomeftp://ftp.ensembl.org/pub/release-73/fasta/homo_sapiens/dna/Homo_sapiens.GRCh37.73.dna.toplevel.fa.gzGRCh37/hg19
dbSNPhttps://www.ncbi.nlm.nih.gov/projects/SNP/144b
1000Genomehttp://www.1000genomes.org/v73
Clinvarftp://ftp.ncbi.nih.gov/snp/organisms/human_9606_b144_GRCh37%20p13/VCF/clinical_vcf_set144

3.4 Bioinformatics software


Analysis item Software Version/date
Quality controlFastQC0.10.1
AlignmentBWA0.7.10
AlignmentSAMtools0.1.19
Duplicates removePicard1.119
SNP/Indel callingGATK3.7
SNP/Indel annotationSnpEff4.1


4. Results


4.1 Sample information


FamilySamplePaaatient/Normalgender
aaaXYYNM
aaaJCFNF
aaaJCXPF
bbbXYLNM
bbbXYJNF
bbbLDH1494PF

document location: summary/1_RawData/sample_info_mendelian.xlsx


4.2 Quality control

SampleRaw DataValid DataRaw depth(x)Valid%Q20%Q30%GC%
ReadBaseReadBase
JCF19156476028.73G18831553228.25G495.3498.3098.3696.2945.94
JCX14848822422.27G14603632221.91G383.9798.3598.5196.5645.83
LDH149415559929823.34G15375134623.06G402.4198.8196.6892.4650.83
XYJ18837868228.26G18546716027.82G487.2498.4598.5296.5546.56
XYL17733360626.60G17474039426.21G458.6298.5498.6496.8046.57
XYY20563948430.85G20213618630.32G531.9098.3096.7992.9845.84

document location: summary/1_SequencingData_Overview/ReadsQC.xlsx


4.3 Sequencing depth



document location: summary/2_MappedData/ReadsDepthCoverage.png


Depth of coverage on each chromosome:


Depth of coverage=covered total length/total length of all exons on each chromosome


document location: summary/2_MappedData/DepthCoverageByChr.png


4.4 Statistics of mapped reads


TermXYYJCFJCXXYLXYJLDH1494
Total205639484 (100.00%)191564760 (100.00%)148488224 (100.00%)177333606 (100.00%)188378682 (100.00%)155599298 (100.00%)
Duplicate31990792 (15.56%)45320420 (23.66%)37297953 (25.12%)40737042 (22.97%)38944025 (20.67%)10475984 (6.73%)
Mapped196967994 (95.78%)183638972 (95.86%)142402263 (95.90%)170120357 (95.93%)180797642 (95.98%)148039614 (95.14%)
TARGET_TERRITORY607001536070015360700153607001536070015358947532
NEAR_AMPLICON_BASES556539049950456444103846665291421159775647421253094225104036
NEAR_AMPLICON_BASES+ TARGET_TERRITORY562609065251063445633907365444427229790948028254624284051568
PF_UQ_READS_ALIGNED196967994183638972142402263170120357180797642148039614
ON_AMPLICON_BASES12023759212115610319649153494977113630574101187533499113235785973
MEAN_TARGET_COVERAGE201.48193.76153.53190.65199.16228.69
PCT_TARGET_BASES_30X96.48%96.23%95.13%95.78%96.13%96.20%
PCT_TARGET_BASES_20X97.07%96.92%96.37%96.65%96.84%96.68%
PCT_TARGET_BASES_10X97.50%97.43%97.21%97.25%97.35%97.09%
PCT_TARGET_BASES_2X97.90%97.88%97.75%97.70%97.77%97.70%


Table Description:

Term Description
TotalNumber of total reads
DuplicateNumber of duplicate reads
MappedNumber of mapped reads on reference genome
TARGET_TERRITORYNumber of bases on target region
NEAR_AMPLICON_BASESNumber of bases on flanking region of target
NEAR_AMPLICON_BASES+TARGET_TERRITORYNA
PF_UQ_READS_ALIGNEDUnique reads mapped on target region
ON_AMPLICON_BASESNumber of mapped on amplicon
MEAN_TARGET_COVERAGEMean coverage of target region
PCT_TARGET_BASES_30Xpercentage of base>=30x on target region
PCT_TARGET_BASES_20Xpercentage of base>=20x on target region
PCT_TARGET_BASES_10Xpercentage of base>=10x on target region
PCT_TARGET_BASES_2Xpercentage of base>=2x on target region

document location: summary/2_MappedData/MappedStatistics.xlsx


Depth of coverage on each sample:

document location: summary/2_MappedData/DepthCoverageByTarget.png


4.5 Variant calling


A single-nucleotide polymorphism, often abbreviated to SNP, is a variation in a single nucleotide that occurs at a specific position in the genome including transition and transversion, where each variation is present to some appreciable degree within a population (e.g. > 1%).

For example, at a specific base position in the human genome, the base C may appear in most individuals, but in a minority of individuals, the position is occupied by base A. There is a SNP at this specific base position, and the two possible nucleotide variations – C or A – are said to be alleles for this base position.

SNPs underlie differences in our susceptibility to disease; a wide range of human diseases, e.g. sickle-cell anemia, β-thalassemia and cystic fibrosis result from SNPs. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations. For example, a single base mutation in the APOE (apolipoprotein E) gene is associated with a higher risk for Alzheimer's disease.

A single-nucleotide variant (SNV) is a variation in a single nucleotide without any limitations of frequency and may arise in somatic cells. A somatic single nucleotide variation (e.g., caused by cancer) may also be called a single-nucleotide alteration.

Indel is a molecular biology term for an insertion or deletion of bases in the genome of an organism. It is classified among small genetic variations, measuring from 1 to 10 000 base pairs in length, including insertion and deletion events that may be separated by many years, and may not be related to each other in any way. A microindel is defined as an Indel that results in a net change of 1 to 50 nucleotides.

In coding regions of the genome, unless the length of an Indel is a multiple of 3, it will produce a frameshift mutation. For example, a common microindel which results in a frameshift causes Bloom syndrome in the Jewish or Japanese population. Indels can be contrasted with a point mutation. An Indel inserts and deletes nucleotides from a sequence, while a point mutation is a form of substitution that replaces one of the nucleotides without changing the overall number in the DNA. Indels can also be contrasted with Tandem Base Mutations (TBM), which may result from fundamentally different mechanisms. A TBM is defined as a substitution at adjacent nucleotides (primarily substitutions at two adjacent nucleotides, but substitutions at three adjacent nucleotides have been observed.

Indels, being either insertions, or deletions, can be used as genetic markers in natural populations, especially in phylogenetic studies. It has been shown that genomic regions with multiple Indels can also be used for species-identification procedures.

An Indel change of a single base pair in the coding part of an mRNA results in a frameshift during mRNA translation that could lead to an inappropriate (premature) stop codon in a different frame. Indels that are not multiples of 3 are particularly uncommon in coding regions but relatively common in non-coding regions. There are approximately 192-280 frameshifting Indels in each person. Indels are likely to represent between 16% and 25% of all sequence polymorphisms in humans. In fact, in most known genomes, including humans, Indel frequency tends to be markedly lower than that of single nucleotide polymorphisms (SNP), except near highly repetitive regions, including homopolymers and microsatellites.

The term "Indel" has been co-opted in recent years by genome scientists for use in the sense described above. This is a change from its original use and meaning, which arose from systematics. In systematics, researchers could find differences between sequences, such as from two different species. But it was impossible to infer if one species lost the sequence or the other species gained it. For example, species A has a run of 4 G nucleotides at a locus and species B has 5 G's at the same locus. If the mode of selection is unknown, one can not tell if species A lost one G (a "deletion" event") or species B gained one G (an "insertion" event). When one cannot infer the phylogenetic direction of the sequence change, the sequence change event is referred to as an "Indel".


4.5.1 Statistics of SNP in position


SNV ClassNON SYNONYMOUS CODINGSTART GAINEDSTART LOSTSTOP GAINEDSTOP LOSTSYNONYMOUS CODING
aaa389081007733974842915
bbb419711084833924746298
SNV PosDOWNSTREAMINTRONSPLICE SITE ACCEPTORUPSTREAMUTR 3 PRIMEUTR 5 PRIME
aaa9733619966018677473140118348
bbb10481321549720683490151848861


High-Impact Effects Moderate-Impact Effects Low-Impact Effects
SPLICE_SITE_ACCEPTORNON_SYNONYMOUS_CODINGSYNONYMOUS_START
SPLICE_SITE_DONORCODON_CHANGE (note: this effect is used by SnpEff only for MNPs, not SNPs)NON_SYNONYMOUS_START
START_LOSTtd>CODON_INSERTIONSTART_GAINED
EXON_DELETEDCODON_CHANGE_PLUS_CODON_INSERTIONSYNONYMOUS_CODING
FRAME_SHIFTCODON_DELETIONSYNONYMOUS_STOP
STOP_GAINEDCODON_CHANGE_PLUS_CODON_DELETIONNON_SYNONYMOUS_STOP
STOP_LOSTUTR_5_DELETED
UTR_3_DELETED

document location: summary/3_VariantData/SNP_INDEL_PositionType_VariantsType.xlsx



document location: summary/3_VariantData/*/*.SNV.png


4.5.2 Statistics of SNP typies


Tips: Ts means transition and Tv means transition.


Statistics of variant typies in SNP:


Sampleallgenotype.Hetgenotype.Homnovelin dbSNPnovel_proportiondbSNP_proportionTsTvnovel.Tsnovel.Tv
aaa7781155830219814797730140.060.94547282321630601743
bbb8365762352213055267783900.060.94589012489633291947

document location: summary/3_VariantData/VariantsType_SNP.xlsx



document location: summary/3_VariantData/*/*.SNP_VariantsType.png


4.5.3 Annotation for SNP


All SNPs were annotated by SnpEff in VCF format. document location: summary/3_VariantData/*/*.snp.annotation.fixed.function.vcf


VCF format Description:

Term Description
CHROMchromosome id
POS IDchromosome position
REFreference allele
ALTalternative allele
QUALquality
FILTERfilter
INFOinformation
ADAllelic depths
DPApproximate read depth
GQGenotype Quality
GTgenotype
PLPhred-scaled likelihoods

4.5.4 Statistics of Indel in position


INDEL ClassCODON CHANGE PLUS CODON DELETIONCODON CHANGE PLUS CODON INSERTIONCODON DELETIONCODON INSERTIONFRAME SHIFTFRAME SHIFT+STOP GAINEDFRAME SHIFT+STAET LOST
aaa256172126206466246
bbb307174136195524246
INDEL PosDOWNSTREAMINTRONSPLICE SITE ACCEPTORSPLICE SITE DONORUPSTREAMUTR 3 PRIMEUTR 5 PRIME
aaa886324244163326958935685
bbb9575261881692876791040720


High-Impact Effects Moderate-Impact Effects Low-Impact Effects
SPLICE_SITE_ACCEPTORNON_SYNONYMOUS_CODINGSYNONYMOUS_START
SPLICE_SITE_DONORCODON_CHANGE (note: this effect is used by SnpEff only for MNPs, not SNPs)NON_SYNONYMOUS_START
START_LOSTtd>CODON_INSERTIONSTART_GAINED
EXON_DELETEDCODON_CHANGE_PLUS_CODON_INSERTIONSYNONYMOUS_CODING
FRAME_SHIFTCODON_DELETIONSYNONYMOUS_STOP
STOP_GAINEDCODON_CHANGE_PLUS_CODON_DELETIONNON_SYNONYMOUS_STOP
STOP_LOSTUTR_5_DELETED
UTR_3_DELETED

document location: summary/3_VariantData/SNP_INDEL_PositionType_VariantsType.xlsx



document location: summary/3_VariantData/*/*.INDEL.png


4.5.5 Statistics of Indel typies


Statistics of variant typies in Indel:


Sampleallgenotype.Hetgenotype.Homnovelin dbSNPnovel_proportiondbSNP_proportion
aaa60093945206496950400.160.84
bbb642744222005110453230.170.83

document location: summary/3_VariantData/VariantsType_INDEL.xlsx



document location: summary/3_VariantData/*/*.INDEL_VariantsType.png


4.5.6 Annotation for Indel


All Indels were annotated by SnpEff in VCF format. document location: summary/3_VariantData/*/*.indel.annotation.fixed.function.vcf


VCF format Description:

Term Description
CHROMchromosome id
POS IDchromosome position
REFreference allele
ALTalternative allele
QUALquality
FILTERfilter
INFOinformation
ADAllelic depths
DPApproximate read depth
GQGenotype Quality
GTgenotype
PLPhred-scaled likelihoods

4.6 Annotation for mutation sites


4.6.1 dbSNP database


The Single Nucleotide Polymorphism Database (dbSNP) is a free public archive for genetic variation within and across different species developed and hosted by the National Center for Biotechnology Information (NCBI) in collaboration with the National Human Genome Research Institute (NHGRI). Although the name of the database implies a collection of one class of polymorphisms only (i.e., single nucleotide polymorphisms (SNPs)), it in fact contains a range of molecular variation: (1) SNPs, (2) short deletion and insertion polymorphisms (indels/DIPs), (3) microsatellite markers or short tandem repeats (STRs), (4) multinucleotide polymorphisms (MNPs), (5) heterozygous sequences, and (6) named variants. The dbSNP accepts apparently neutral polymorphisms, polymorphisms corresponding to known phenotypes, and regions of no variation. It was created in September 1998 to supplement GenBank, NCBI’s collection of publicly available nucleic acid and protein sequences.

As of build 131 (available February 2010), dbSNP had amassed over 184 million submissions representing more than 64 million distinct variants for 55 organisms, including Homo sapiens, Mus musculus, Oryza sativa, and many other species. A full list of organisms and the number of submissions for each can be found at: https://www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi


document location: summary/4_VariantMultiAnno/*/SNP/*.snp.dbSNP.xlsx


4.6.2 1000 Genome database


The 1000 Genomes Project (abbreviated as 1KGP), launched in January 2008, was an international research effort to establish by far the most detailed catalogue of human genetic variation. Scientists planned to sequence the genomes of at least one thousand anonymous participants from a number of different ethnic groups within the following three years, using newly developed technologies which were faster and less expensive. In 2010, the project finished its pilot phase, which was described in detail in a publication in the journal Nature (PMID: 20981092). In 2012, the sequencing of 1092 genomes was announced in a Nature publication (PMID: 23128226). In 2015, a paper published in Nature (PMID: 26432245) reported results and the completion of the project and opportunities for future research. Many rare variations, restricted to closely related groups, were identified, and eight structural-variation classes were analyzed.

The project unites multidisciplinary research teams from institutes around the world, including China, Italy, Japan, Kenya, Nigeria, Peru, the United Kingdom, and the United States. Each will contribute to the enormous sequence dataset and to a refined human genome map, which will be freely accessible through public databases to the scientific community and the general public alike.

By providing an overview of all human genetic variation, the consortium will generate a valuable tool for all fields of biological science, especially in the disciplines of genetics, medicine, pharmacology, biochemistry, and bioinformatics.

High frequency mutations (MAF>5%) were filtered. We remained low frequency mutations (0.5%<=MAF<=5%) as candidates for downstream analysis.


document location: summary/4_VariantMultiAnno/*/SNP/*.snp.dbSNP.xlsx


4.6.3 Filtering according to coding region


Those mutations on CDS, exon or splicing region (±10bp) will be chosen as candidates for downstream analysis.


document location: summary/4_VariantMultiAnno/*/SNP/*.snp.dbSNP.KGenome.func.xlsx


4.6.4 SIFT annotater


The SIFT (sorting intolerant from tolerant) algorithm helps bridge the gap between mutations and phenotypic variations by predicting whether an amino acid substitution is deleterious. SIFT has been used in disease, mutation and genetic studies, and a protocol for its use has been published on Nature Protocols (PMID: 26633127). Predicts whether an amino acid substitution affects protein function. SIFT prediction is based on the degree of conservation of amino acid residues in sequence alignments derived from closely related sequences, collected through PSI-BLAST. SIFT can be applied to naturally occurring nonsynonymous polymorphisms or laboratory-induced missense mutations. The range of score is from 0 to 1. Mutations with score>0.05 are tolerant and have minor impact on protein function. Detrimental mutation with score<0.05 have a big influence on protein function.


document location: summary/4_VariantMultiAnno/*/SNP/*.snp.dbSNP.KGenome.func.syn.xlsx


4.7 De novo mutation


De novo mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing (WES) approaches. De novo mutations play a prominent part in rare and common forms of diseases, including intellectual disability, autism and schizophrenia. De novo mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population. These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies (PMID: 22805709 ).

In order to prove whether those mutations are correlation with some diseases, we calculate different mutation rate of same gene according mutation rate of known gene, gene length and sex ratio of patients.


ChrStart_PositionRefAltrsIDGeneRegionGeneSymbolGO_BPGO_CCGO_MFKEGGImpactJCFJCXXYY
chr11859131CTrs4648734exonicC1orf222....nonsynonymous SNV0/0:194,0:194:99:0,430,55190/0:142,0:142:99:0,310,40500/1:156,139:297:99:3311,0,3705
chr12526746AGrs3748816exonicMMEL1proteolysisextracellular region,endoplasmic reticulum,Golgi apparatus,integral to membranemetalloendopeptidase activity,metal ion binding.nonsynonymous SNV0/0:149,3:152:99:0,240,40770/0:146,0:146:99:0,313,41440/1:108,95:204:99:2300,0,2603
chr13410581GArs61746168exonicMEGF6....nonsynonymous SNV0/0:129,0:129:99:0,250,34100/0:98,0:98:99:0,199,26780/1:81,71:152:99:1725,0,2071
chr13410644AGrs61742508exonicMEGF6....nonsynonymous SNV0/0:75,0:75:99:0,163,21420/0:59,3:62:39:0,39,14670/1:51,42:93:99:1018,0,1243
chr13421897AGrs2821008exonicMEGF6....nonsynonymous SNV0/0:111,0:111:99:0,244,31740/0:84,0:84:99:0,193,25070/1:83,63:146:99:1517,0,2055
chr13753136ATrs2275824exonicCEP104.centriole..nonsynonymous SNV0/0:45,0:45:99:0,108,13720/0:62,0:62:99:0,126,17050/1:37,29:66:99:757,0,881
chr14772717GArs242056exonicAJAP1cell adhesionadherens junction,integral to membrane,basolateral plasma membrane,apical plasma membrane..nonsynonymous SNV0/0:105,1:106:99:0,205,30460/0:45,0:45:96:0,96,12770/1:47,50:97:99:1169,0,1291
chr16615504AGrs199797470exonicTAS1R1detection of chemical stimulus involved in sensory perception of taste,sensory perception of umami tasteplasma membrane,integral to membranetaste receptor activity,protein heterodimerization activityTaste transductionnonsynonymous SNV0/0:95,0:95:99:0,196,26200/0:63,0:63:99:0,126,17020/1:71,79:150:99:1817,0,1759
chr16635306GArs34160967exonicTAS1R1detection of chemical stimulus involved in sensory perception of taste,sensory perception of umami tasteplasma membrane,integral to membranetaste receptor activity,protein heterodimerization activityTaste transductionnonsynonymous SNV0/0:212,0:212:99:0,463,61240/0:165,1:166:99:0,299,44250/1:150,170:320:99:4154,0,3867
chr18420212TG.exonicREREchromatin remodeling,transcription, DNA-dependent,NLS-bearing substrate import into nucleus,multicellular organismal developmenthistone deacetylase complex,nucleus,nucleolus,mitochondrionchromatin binding,sequence-specific DNA binding transcription factor activity,protein binding,poly-glutamine tract binding,zinc ion binding,sequence-specific DNA binding,metal ion binding.nonsynonymous SNV0/0:52,0:52:99:0,117,15090/0:33,0:33:69:0,69,9060/1:29,23:52:99:589,0,789
chr19034421GArs3765964exonicCA6one-carbon metabolic process,bicarbonate transport,small molecule metabolic processextracellular region,extracellular space,cytoplasmcarbonate dehydratase activity,zinc ion binding,metal ion bindingNitrogen metabolismnonsynonymous SNV0/0:91,2:93:99:0,154,25110/0:71,0:71:99:0,150,20020/1:77,72:149:99:1725,0,1895
chr111014118CTrs45537241exonicC1orf127....nonsynonymous SNV0/0:144,2:146:99:0,241,38110/0:109,0:109:99:0,226,30360/1:108,79:188:99:1694,0,2684
chr111015165AGrs75130475exonicC1orf127....nonsynonymous SNV0/0:46,0:46:99:0,105,13870/0:43,0:43:90:0,90,12040/1:35,42:77:99:968,0,843
chr111982580GArs11555351exonicKIAA2013.integral to membrane..nonsynonymous SNV0/0:118,0:118:99:0,268,34770/0:90,0:90:99:0,196,25950/1:69,71:142:99:1656,0,1855
chr112004663GArs112799470exonicPLOD1response to hypoxia,cellular protein modification process,epidermis development,extracellular matrix organization,hydroxylysine biosynthetic process,oxidation-reduction processendoplasmic reticulum membrane,rough endoplasmic reticulum membraneiron ion binding,procollagen-lysine 5-dioxygenase activity,oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen,L-ascorbic acid binding,protein homodimerization activityLysine degradationnonsynonymous SNV0/0:66,0:66:99:0,132,17520/0:62,0:62:99:0,114,15560/1:58,37:95:99:882,0,1387
chr112009956GArs7551175exonicPLOD1response to hypoxia,cellular protein modification process,epidermis development,extracellular matrix organization,hydroxylysine biosynthetic process,oxidation-reduction processendoplasmic reticulum membrane,rough endoplasmic reticulum membraneiron ion binding,procollagen-lysine 5-dioxygenase activity,oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen,L-ascorbic acid binding,protein homodimerization activityLysine degradationnonsynonymous SNV0/0:96,0:96:99:0,211,27140/0:81,0:81:99:0,163,21540/1:83,58:141:99:1415,0,1925
chr112785295CTrs17038445exonicAADACL3..hydrolase activity.nonsynonymous SNV0/0:91,0:91:99:0,205,26050/0:78,0:78:99:0,172,22410/1:80,57:139:99:1521,0,1977
chr112835168CArs17346571exonicPRAMEF12positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:173,0:173:99:0,361,48090/0:151,1:152:99:0,310,41870/1:92,107:199:99:2645,0,2304
chr112855774AGrs75985223exonicPRAMEF1positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:165,0:165:99:0,355,46720/0:127,0:127:99:0,268,35550/1:201,90:291:99:926,0,4949
chr112907449CGrs78163065exonicHNRNPCL1.nucleus,ribonucleoprotein complexnucleotide binding,RNA binding.nonsynonymous SNV0/0:220,2:222:99:0,374,54690/0:154,0:154:99:0,283,37560/1:144,85:230:99:1894,0,3396
chr112907496TCrs138700801exonicHNRNPCL1.nucleus,ribonucleoprotein complexnucleotide binding,RNA binding.nonsynonymous SNV0/0:189,1:190:99:0,324,47780/0:128,0:128:99:0,232,31700/1:124,87:211:99:1965,0,3147
chr112919064TGrs3204790exonicPRAMEF2positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:149,0:149:99:0,319,42050/0:95,0:95:99:0,199,26380/1:103,132:236:99:3154,0,2497
chr112919872TGrs3204798exonicPRAMEF2positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:117,0:117:99:0,268,35230/0:87,0:87:99:0,181,24220/1:81,73:155:99:1829,0,2085
chr112919891GTrs75411676exonicPRAMEF2positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.stopgain SNV0/0:129,0:129:99:0,289,37800/0:93,0:93:99:0,184,24860/1:85,81:166:99:1929,0,2061
chr112919934AGrs3204805exonicPRAMEF2positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:147,0:147:99:0,307,40820/0:95,0:95:99:0,199,26490/1:94,86:180:99:2120,0,2364
chr112939495ATrs150289150exonicPRAMEF4positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:202,0:202:99:0,337,44160/0:160,0:161:99:0,262,34970/1:253,148:402:99:2281,0,5595
chr112939535CTrs72474509exonicPRAMEF4positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:206,0:206:99:0,403,52570/0:160,0:160:99:0,313,41110/1:255,148:408:99:2321,0,5793
chr112939624CGrs200663811exonicPRAMEF4positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:162,7:170:99:0,283,46150/0:128,7:135:99:0,164,35740/1:128,107:235:99:1969,0,3309
chr113365976GC.exonicPRAMEF5positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:160,1:161:33:0,33,3100/0:101,0:101:12:0,12,1140/1:142,68:210:12:114,0,12
chr113365992CT.exonicPRAMEF5positive regulation of cell proliferation,negative regulation of apoptotic process,negative regulation of cell differentiation,negative regulation of transcription, DNA-dependent,negative regulation of retinoic acid receptor signaling pathway.retinoic acid receptor binding.nonsynonymous SNV0/0:150,2:153:27:0,27,2500/0:92,0:92:6:0,6,520/1:139,63:203:12:114,0,12
chr113474934GArs201446830exonicPRAMEF18....nonsynonymous SNV0/0:171,0:171:99:0,196,22950/0:92,0:92:99:0,126,15030/1:91,85:176:99:1508,0,886
chr113474951CGrs201753501exonicPRAMEF18....nonsynonymous SNV0/0:140,38:178:99:0,184,27970/0:90,15:105:99:0,184,22370/1:77,110:187:99:1626,0,1277
chr113475186AGrs201814272exonicPRAMEF18....nonsynonymous SNV0/0:82,3:85:72:0,72,7740/0:68,1:69:99:0,105,11000/1:57,52:110:99:534,0,978
chr115438990GArs10803354exonicKAZNkeratinizationcornified envelope,nucleus,nucleolus,cytoplasm,desmosome,nuclear membrane,intracellular membrane-bounded organelle..nonsynonymous SNV0/0:138,0:138:99:0,289,38540/0:78,2:80:99:0,124,21600/1:83,64:147:99:1467,0,1933
chr116460381GArs376402047exonicEPHA2skeletal system development,angiogenesis,vasculogenesis,osteoblast differentiation,apoptotic process,cell adhesion,multicellular organismal development,regulation of lamellipodium assembly,notochord formation,neural tube development,neuron differentiation,keratinocyte differentiation,osteoclast differentiation,activation of Rac GTPase activity,mammary gland epithelial cell proliferation,regulation of cell adhesion mediated by integrin,protein kinase B signaling cascade,regulation of blood vessel endothelial cell migration,regulation of angiogenesis,bone remodeling,ephrin receptor signaling pathway,axial mesoderm formation,negative regulation of protein kinase B signaling cascade,notochord cell development,cell chemotaxis,branching involved in mammary gland duct morphogenesis,lens fiber cell morphogenesis,regulation of ERK1 and ERK2 cascade,response to growth factor stimulus,positive regulation of establishment of protein localization in plasma membraneplasma membrane,integral to plasma membrane,focal adhesion,leading edge membrane,lamellipodium membrane,ruffle membranetransmembrane receptor protein tyrosine kinase activity,ephrin receptor activity,protein binding,ATP bindingAxon guidancenonsynonymous SNV0/0:79,0:79:99:0,160,21050/0:46,0:46:90:0,90,11940/1:58,57:118:99:1495,0,1324
chr116577908GCrs12069239exonicFBXO42....nonsynonymous SNV0/0:145,0:145:99:0,328,42740/0:120,0:120:99:0,256,33830/1:104,88:192:99:2259,0,2671
chr116736132TCrs4661746exonicSPATA21..calcium ion binding.nonsynonymous SNV0/0:57,0:57:99:0,132,17180/0:58,0:58:99:0,123,16510/1:40,51:93:99:1249,0,1110
chr117296361CGrs79354809exonicCROCCcell cycle,protein localization,cell projection organization,centrosome organizationcytoplasm,centrosome,centriole,plasma membrane,actin cytoskeleton,ciliary rootletstructural molecule activity,protein binding,kinesin binding.nonsynonymous SNV0/0:98,0:98:99:0,208,26800/0:49,0:49:99:0,99,13070/1:65,79:144:99:1958,0,1493
chr117657534GArs11203366exonicPADI4transcription, DNA-dependent,regulation of transcription, DNA-dependent,cellular protein modification process,chromatin modification,peptidyl-citrulline biosynthetic process from peptidyl-argininenucleus,cytoplasmprotein-arginine deiminase activity,calcium ion binding.nonsynonymous SNV0/0:102,0:102:99:0,220,27730/0:105,2:107:99:0,157,26180/1:64,75:139:99:1832,0,1511
chr117657616TCrs11203367exonicPADI4transcription, DNA-dependent,regulation of transcription, DNA-dependent,cellular protein modification process,chromatin modification,peptidyl-citrulline biosynthetic process from peptidyl-argininenucleus,cytoplasmprotein-arginine deiminase activity,calcium ion binding.nonsynonymous SNV0/0:85,1:86:99:0,156,24250/0:68,0:68:99:0,150,19810/1:55,64:119:99:1590,0,1414
chr117660499GCrs874881exonicPADI4transcription, DNA-dependent,regulation of transcription, DNA-dependent,cellular protein modification process,chromatin modification,peptidyl-citrulline biosynthetic process from peptidyl-argininenucleus,cytoplasmprotein-arginine deiminase activity,calcium ion binding.nonsynonymous SNV0/0:85,2:87:99:0,106,22270/0:63,1:64:99:0,135,17800/1:71,57:129:99:1363,0,1925
chr120246876CTrs61729970exonicPLA2G2E....nonsynonymous SNV0/0:106,1:107:99:0,186,28700/0:59,1:60:96:0,96,16410/1:79,67:147:99:1681,0,1832
chr125634143TCrs2427766exonicRHD.integral to plasma membraneammonium transmembrane transporter activity.nonsynonymous SNV0/0:33,0:33:78:0,78,10030/0:18,0:18:42:0,42,5500/1:27,24:51:99:629,0,683
chr126694245TCrs10794531exonicZNF683transcription, DNA-dependent,regulation of transcription, DNA-dependentnucleusDNA binding,zinc ion binding,metal ion binding.nonsynonymous SNV0/0:96,0:96:99:0,202,26350/0:65,0:65:99:0,141,18580/1:53,62:115:99:1413,0,1311
chr126694260TCrs10794532exonicZNF683transcription, DNA-dependent,regulation of transcription, DNA-dependentnucleusDNA binding,zinc ion binding,metal ion binding.nonsynonymous SNV0/0:101,0:101:99:0,202,26820/0:75,0:75:99:0,150,20190/1:53,64:118:99:1608,0,1254
chr131425154TCrs144369611exonicPUM1regulation of translation,post-Golgi vesicle-mediated transport,cellular membrane organizationcytosolRNA binding.nonsynonymous SNV0/0:107,0:107:99:0,220,29690/0:74,0:74:99:0,163,21620/1:79,66:146:99:1554,0,2020
chr133820134CTrs12026290exonicPHC2multicellular organismal development,spermatogenesisnucleus,nucleolus,PcG protein complex,PRC1 complexDNA binding,protein binding,zinc ion binding,metal ion binding.nonsynonymous SNV0/0:86,0:86:99:0,184,24380/0:72,0:72:99:0,147,19760/1:53,54:108:99:1397,0,1353
chr134663208CGrs1382602exonicC1orf94..protein binding.nonsynonymous SNV0/0:163,3:166:99:0,290,46030/0:116,0:116:99:0,256,34010/1:106,105:211:99:2523,0,2810
chr134663411CGrs1414474exonicC1orf94..protein binding.nonsynonymous SNV0/0:97,0:97:99:0,199,26420/0:80,0:80:99:0,163,21890/1:77,44:121:99:1068,0,1982
chr136807481CTrs3795498exonicSTK40.nucleus,nucleolus,cytoplasmprotein serine/threonine kinase activity,protein binding,ATP binding.nonsynonymous SNV0/0:117,0:117:99:0,253,32740/0:84,0:84:99:0,178,23250/1:76,74:150:99:1799,0,1885
chr136886117CTrs2275477exonicOSCP1transportbasal plasma membrane..nonsynonymous SNV0/0:80,0:80:99:0,160,21410/0:74,0:74:99:0,144,19360/1:69,37:106:99:974,0,1688
chr136898067TCrs34409118exonicOSCP1transportbasal plasma membrane..nonsynonymous SNV0/0:57,0:57:99:0,135,17000/0:39,0:39:93:0,93,11760/1:42,38:80:99:947,0,1063
chr138023316CTrs11749exonicDNALI1cellular component movement,single fertilizationcytoplasm,axonemal dynein complex,axonememicrotubule motor activityHuntington's diseasenonsynonymous SNV0/0:149,2:151:99:0,268,40880/0:87,0:87:99:0,178,23920/1:94,93:187:99:2242,0,2375
chr138227268GTrs56276182exonicEPHA10biological_processextracellular region,integral to plasma membrane,integral to membraneephrin receptor activity,transmembrane-ephrin receptor activity,protein binding,ATP binding.nonsynonymous SNV0/0:83,0:83:99:0,184,23410/0:63,0:63:99:0,144,18120/1:63,54:117:99:1460,0,1491
chr139339449CTrs12127091exonicGJA9cell communicationconnexon complex,integral to membrane..nonsynonymous SNV0/0:130,0:130:99:0,277,36170/0:114,0:114:99:0,229,30670/1:71,90:162:99:2260,0,1691
chr139340282CTrs880303exonicGJA9cell communicationconnexon complex,integral to membrane..nonsynonymous SNV0/0:114,0:114:99:0,256,32990/0:110,0:111:99:0,235,30650/1:90,81:171:99:1868,0,2299
chr139352271GTrs2147914exonicRHBDL2proteolysisplasma membrane,integral to membraneserine-type endopeptidase activity.nonsynonymous SNV0/0:176,2:179:99:0,356,51500/0:119,0:119:99:0,265,34830/1:105,111:216:99:2800,0,2728
chr140702994GA.exonicRLFtranscription, DNA-dependent,regulation of transcription, DNA-dependent,DNA mediated transformation,DNA integration,positive regulation of transcription, DNA-dependent,positive regulation of transcription from RNA polymerase II promoter,chromosome organizationnucleusDNA binding,protein binding,zinc ion binding,metal ion binding.nonsynonymous SNV0/0:65,0:65:99:0,141,18740/0:51,0:51:99:0,111,14710/1:42,35:77:99:943,0,1094
chr142898843AGrs1034268exonicZMYND12.intracellularzinc ion binding,metal ion binding.nonsynonymous SNV0/0:86,0:86:99:0,169,23020/0:64,0:64:99:0,132,17780/1:59,73:132:99:1842,0,1478
chr143201534GArs4660658exonicCLDN19visual perception,calcium-independent cell-cell adhesion,neuronal action potential propagation,apical junction assembly,response to stimulusnucleus,cytoplasm,tight junction,integral to membrane,basolateral plasma membrane,apical junction complexstructural molecule activity,identical protein bindingHepatitis Cnonsynonymous SNV0/0:76,0:76:99:0,169,21650/0:58,3:61:60:0,60,16380/1:54,45:99:99:1247,0,1336
chr143212869ATrs3738496exonicLEPRE1negative regulation of cell proliferation,cell growth,extracellular matrix organization,collagen fibril organization,regulation of ossificationcellular_component,proteinaceous extracellular matrix,nucleus,endoplasmic reticulum lumenmolecular_function,iron ion binding,oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen,procollagen-proline 3-dioxygenase activity,L-ascorbic acid binding.nonsynonymous SNV0/0:168,0:168:99:0,361,48360/0:112,0:112:99:0,241,32250/1:137,118:255:99:2812,0,3342
chr143803863CTrs6087exonicMPL....nonsynonymous SNV0/0:112,0:112:99:0,238,30300/0:85,0:85:99:0,163,21650/1:69,74:143:99:1888,0,1462
chr144466606GArs2248632exonicSLC6A9transport,transmembrane transportplasma membrane,integral to plasma membrane,membraneneurotransmitter:sodium symporter activity,glycine:sodium symporter activity.nonsynonymous SNV0/0:238,1:239:99:0,485,65000/0:172,0:172:99:0,349,47170/1:125,121:246:99:2895,0,3166
chr146500744GCrs3737737exonicMAST2protein phosphorylation,regulation of interleukin-12 biosynthetic process,spermatid differentiationcytoplasm,plasma membrane,microtubule cytoskeletonmagnesium ion binding,protein serine/threonine kinase activity,protein binding,ATP binding,microtubule binding,phosphatase binding.nonsynonymous SNV0/0:122,1:123:99:0,240,35400/0:83,0:83:99:0,190,24460/1:73,78:151:99:1945,0,1765
chr147139103CTrs1025806exonicTEX38.integral to membrane..nonsynonymous SNV0/0:170,0:170:99:0,373,49350/0:110,0:110:99:0,247,32330/1:123,103:227:99:2448,0,3103
chr147399670GTrs145599381exonicCYP4A11long-chain fatty acid metabolic process,renal water homeostasis,pressure natriuresis,fatty acid metabolic process,leukotriene metabolic process,xenobiotic metabolic process,arachidonic acid metabolic process,epoxygenase P450 pathway,positive regulation of icosanoid secretion,leukotriene B4 catabolic process,cellular lipid metabolic process,small molecule metabolic process,sodium ion homeostasis,oxidation-reduction processcytoplasm,endoplasmic reticulum membrane,apical plasma membrane,intracellular membrane-bounded organelleiron ion binding,arachidonic acid epoxygenase activity,electron carrier activity,alkane 1-monooxygenase activity,heme binding,leukotriene-B4 20-monooxygenase activity,arachidonic acid omega-hydroxylase activityVascular smooth muscle contractionnonsynonymous SNV0/0:300,0:300:99:0,587,76260/0:260,0:260:99:0,524,68270/1:141,83:224:99:1737,0,3367
chr147603188CTrs76011927exonicCYP4A22....nonsynonymous SNV0/0:104,0:104:99:0,223,29240/0:106,0:106:99:0,211,28300/1:93,89:183:99:2319,0,2270
chr147834209GTrs35687416exonicCMPK1UMP biosynthetic process,pyrimidine ribonucleotide biosynthetic process,nucleobase-containing small molecule interconversion,small molecule metabolic process,nucleobase-containing small molecule metabolic processnucleus,cytoplasm,cytosolcytidylate kinase activity,uridine kinase activity,ATP binding,phosphotransferase activity, phosphate group as acceptorMetabolic pathwaysnonsynonymous SNV0/0:78,0:78:99:0,202,25320/0:77,0:77:99:0,169,22260/1:94,70:164:99:1664,0,2198
chr153153432TCrs443751exonicCOA7....nonsynonymous SNV0/0:152,0:153:99:0,316,42580/0:101,0:101:99:0,202,27520/1:82,100:183:99:2526,0,2033
chr153535478GArs1288386exonicPODNnegative regulation of cell proliferation,negative regulation of cell migrationproteinaceous extracellular matrix,extracellular space,cytoplasmcollagen binding.nonsynonymous SNV0/0:37,0:37:78:0,78,10210/0:26,0:26:57:0,57,7290/1:51,29:80:99:721,0,1234
chr153544513CTrs12567021exonicPODNnegative regulation of cell proliferation,negative regulation of cell migrationproteinaceous extracellular matrix,extracellular space,cytoplasmcollagen binding.nonsynonymous SNV0/0:160,0:161:99:0,364,45860/0:129,0:129:99:0,271,34980/1:100,109:209:99:2913,0,2385
chr153553754TCrs1288401exonicSLC1A7ion transport,dicarboxylic acid transport,L-glutamate transport,transmembrane transportplasma membrane,integral to membraneL-glutamate transmembrane transporter activity,sodium:dicarboxylate symporter activityGlutamatergic synapsenonsynonymous SNV0/0:71,0:71:99:0,175,22520/0:64,1:65:99:0,110,18660/1:55,60:115:99:1556,0,1548
chr153676401TGrs2229291exonicCPT2fatty acid beta-oxidation,carnitine shuttle,cellular lipid metabolic process,small molecule metabolic process,regulation of fatty acid oxidationnucleus,nucleolus,mitochondrion,mitochondrial inner membranecarnitine O-palmitoyltransferase activityPPAR signaling pathwaynonsynonymous SNV0/0:72,0:72:99:0,184,23600/0:74,0:74:99:0,178,23260/1:72,60:132:99:1603,0,2125
chr153676448GArs1799821exonicCPT2fatty acid beta-oxidation,carnitine shuttle,cellular lipid metabolic process,small molecule metabolic process,regulation of fatty acid oxidationnucleus,nucleolus,mitochondrion,mitochondrial inner membranecarnitine O-palmitoyltransferase activityPPAR signaling pathwaynonsynonymous SNV0/0:89,0:89:99:0,205,25740/0:79,0:79:99:0,178,22550/1:65,54:119:99:1423,0,1612
chr155075341GArs41297137exonicFAM151Abiological_processmembrane,integral to membranemolecular_function.nonsynonymous SNV0/0:78,0:78:99:0,169,21820/0:63,0:63:99:0,141,18230/1:57,61:119:99:1638,0,1379
chr155266797GCrs671108exonicTTC22....nonsynonymous SNV0/0:177,0:177:99:0,367,48950/0:128,0:128:99:0,253,34350/1:111,115:227:99:2690,0,2893
chr157257765GCrs147827833exonicC1orf168....nonsynonymous SNV0/0:88,0:88:99:0,196,25690/0:57,0:57:99:0,123,16300/1:52,51:104:99:1335,0,1313
chr158939634GArs12407003exonicOMA1diet induced thermogenesis,glucose metabolic process,misfolded or incompletely synthesized protein catabolic process,lipid metabolic process,response to stress,negative regulation of mitochondrial fusion,mitochondrial protein processing,cristae formation,energy homeostasismitochondrial inner membrane,integral to membrane,mitochondrial membranemetalloendopeptidase activity,metal ion binding.nonsynonymous SNV0/0:189,0:189:99:0,385,50840/0:136,0:136:99:0,280,36630/1:127,137:264:99:3289,0,3082
chr160314067GA.exonicHOOK1microtubule cytoskeleton organization,endosome organization,lysosome organization,multicellular organismal development,spermatid development,endosome to lysosome transport,protein transport,early endosome to late endosome transportmicrotubule,HOPS complex,FHF complexactin binding,protein binding,microtubule binding,identical protein binding.nonsynonymous SNV0/0:85,0:85:99:0,178,23080/0:62,0:62:99:0,111,15430/1:65,56:122:99:1409,0,1474
chr162673037TCrs7542665exonicL1TD1....nonsynonymous SNV0/0:71,1:72:99:0,135,21230/0:67,0:67:99:0,156,20080/1:55,43:98:99:1045,0,1420
chr162673225GArs7533274exonicL1TD1....nonsynonymous SNV0/0:82,0:82:99:0,172,23000/0:65,0:65:99:0,138,18390/1:45,45:90:99:1198,0,1124
chr175038228ACrs11580409exonicC1orf173....nonsynonymous SNV0/0:165,0:165:99:0,340,45880/0:151,2:153:99:0,274,42160/1:98,113:211:99:3019,0,2377
chr179095526GArs3820093exonicIFI44L....nonsynonymous SNV0/0:101,0:101:99:0,217,28490/0:90,0:90:99:0,202,26390/1:71,97:168:99:2278,0,1734
chr179102726CTrs1981071exonicIFI44L....nonsynonymous SNV0/0:47,0:47:99:0,105,13670/0:53,0:53:99:0,117,15320/1:33,43:76:99:1135,0,865
chr186512536CTrs60891279exonicCOL24A1extracellular matrix organizationextracellular region,collagen,endoplasmic reticulum lumenextracellular matrix structural constituent.nonsynonymous SNV0/0:80,1:83:99:0,120,20170/0:70,0:70:99:0,150,19310/1:60,62:122:99:1566,0,1386
chr189844035TCrs35837853exonicGBP6....nonsynonymous SNV0/0:97,1:98:99:0,180,27580/0:107,0:107:99:0,214,28710/1:84,79:163:99:1903,0,2083
chr189847372GTrs4658359exonicGBP6....nonsynonymous SNV0/0:106,0:106:99:0,238,31310/0:84,1:85:99:0,175,23370/1:86,84:171:99:2073,0,2242
chr189849742ATrs959460exonicGBP6....nonsynonymous SNV0/0:56,0:56:99:0,105,14590/0:52,0:52:99:0,105,14120/1:43,27:71:99:585,0,1195
chr192327045GArs1805110exonicTGFBR3blood vessel development,response to hypoxia,blastocyst development,epithelial to mesenchymal transition,liver development,heart morphogenesis,immune response,transforming growth factor beta receptor signaling pathway,transforming growth factor beta receptor complex assembly,intracellular protein kinase cascade,negative regulation of epithelial cell migration,negative regulation of epithelial to mesenchymal transition,cell growth,cell migration,BMP signaling pathway,positive regulation of transforming growth factor beta receptor signaling pathway,negative regulation of transforming growth factor beta receptor signaling pathway,organ regeneration,response to follicle-stimulating hormone stimulus,response to prostaglandin E stimulus,response to luteinizing hormone stimulus,regulation of protein binding,negative regulation of epithelial cell proliferation,positive regulation of NF-kappaB transcription factor activity,negative regulation of cellular component movement,ventricular cardiac muscle tissue morphogenesis,palate development,cardiac muscle cell proliferation,definitive hemopoiesis,cardiac epithelial to mesenchymal transition,definitive erythrocyte differentiation,heart trabecula formation,pathway-restricted SMAD protein phosphorylationproteinaceous extracellular matrix,extracellular space,endoplasmic reticulum,integral to plasma membrane,external side of plasma membrane,cell surface,inhibin-betaglycan-ActRII complextransforming growth factor beta-activated receptor activity,type II transforming growth factor beta receptor binding,transforming growth factor beta receptor binding,protein binding,glycosaminoglycan binding,heparin binding,coreceptor activity,PDZ domain binding,SMAD binding,activin binding,transforming growth factor beta binding,transforming growth factor beta receptor activity, type III.nonsynonymous SNV0/0:70,0:70:99:0,135,18240/0:45,0:45:90:0,90,12050/1:71,37:110:99:976,0,1666
chr1100575933GArs13375867exonicSASS6centriole replication,centrosome duplicationcentrosome,centrioleprotein binding.nonsynonymous SNV0/0:124,0:124:99:0,247,32770/0:87,0:87:99:0,181,23310/1:72,105:177:99:2490,0,1682
chr1108307727TArs7528153exonicVAV3angiogenesis,vesicle fusion,apoptotic process,response to DNA damage stimulus,integrin-mediated signaling pathway,small GTPase mediated signal transduction,blood coagulation,cell migration,lamellipodium assembly,platelet activation,positive regulation of B cell proliferation,regulation of Rho protein signal transduction,response to drug,positive regulation of GTPase activity,positive regulation of phosphatidylinositol 3-kinase activity,positive regulation of cell adhesion,nerve growth factor receptor signaling pathway,B cell receptor signaling pathway,regulation of small GTPase mediated signal transductioncytosol,plasma membraneSH3/SH2 adaptor activity,GTPase activator activity,epidermal growth factor receptor binding,protein binding,phospholipid binding,Rac guanyl-nucleotide exchange factor activity,metal ion bindingRegulation of actin cytoskeletonnonsynonymous SNV0/0:50,1:51:74:0,74,13690/0:44,0:44:93:0,93,12270/1:44,30:74:99:787,0,1117
chr1109479755GA.exonicCLCC1.nucleus,endoplasmic reticulum,Golgi apparatus,integral to membrane,intracellular membrane-bounded organellechloride channel activity.nonsynonymous SNV0/0:81,0:81:99:0,166,21330/0:47,0:47:90:0,90,11950/1:54,56:110:99:1321,0,1344
chr1111857208GArs3818822exonicCHIApolysaccharide catabolic process,response to acid,production of molecular mediator involved in inflammatory response,chitin metabolic process,chitin catabolic process,cell wall chitin metabolic process,apoptotic process,immune response,digestion,response to fungus,positive regulation of chemokine secretionextracellular space,cytoplasmlysozyme activity,chitinase activity,chitin binding,kinase binding,carbohydrate binding,cation bindingAmino sugar and nucleotide sugar metabolismnonsynonymous SNV0/0:145,0:145:99:0,286,37840/0:102,0:102:99:0,199,26640/1:73,86:159:99:2108,0,1669
chr1111957688TCrs3767607exonicOVGP1carbohydrate metabolic process,chitin catabolic process,single fertilization,female pregnancytransport vesiclechitinase activity,cation binding.nonsynonymous SNV0/0:127,0:127:99:0,295,38260/0:66,0:66:99:0,163,20900/1:80,85:165:99:2127,0,1986
chr1113098534CTrs6658555exonicST7Lnegative regulation of cell growthintegral to membrane..nonsynonymous SNV0/0:106,0:106:99:0,214,28390/0:76,0:76:99:0,147,19890/1:62,69:131:99:1759,0,1421
chr1114249341GA.exonicPHTF1transcription, DNA-dependentnucleus,endoplasmic reticulum,cis-Golgi networkDNA binding,sequence-specific DNA binding transcription factor activity.nonsynonymous SNV0/0:88,0:88:99:0,184,24640/0:53,0:53:99:0,111,14930/1:54,58:112:99:1327,0,1446
chr1117113552TCrs17426456exonicCD58cell adhesion,blood coagulation,cell-cell adhesion,leukocyte migrationplasma membrane,integral to plasma membrane,anchored to membraneprotein bindingCell adhesion molecules (CAMs)nonsynonymous SNV0/0:48,0:48:99:0,99,13390/0:33,0:33:63:0,63,8700/1:45,40:85:99:871,0,1099
chr1117311147CArs699738exonicCD2membrane raft polarization,induction of apoptosis,cell surface receptor signaling pathway,blood coagulation,cell-cell adhesion,natural killer cell activation,positive regulation of myeloid dendritic cell activation,T cell activation,regulation of T cell differentiation,leukocyte migrationextracellular region,plasma membrane,integral to plasma membrane,external side of plasma membrane,internal side of plasma membrane,anchored to plasma membranereceptor activity,protein binding,protein homodimerization activity,eukaryotic cell surface bindingHematopoietic cell lineagenonsynonymous SNV0/0:204,2:206:99:0,368,54760/0:130,0:130:99:0,262,35330/1:117,123:240:99:3131,0,2899
chr1117659277TC.exonicTRIM45.nucleus,nucleolus,cytoplasmzinc ion binding,metal ion binding.nonsynonymous SNV0/0:83,0:83:99:0,181,23640/0:44,0:45:90:0,90,12070/1:53,52:106:99:1403,0,1246
chr1118165691CGrs1630312exonicFAM46C....nonsynonymous SNV0/0:133,0:133:99:0,292,37370/0:116,0:116:99:0,256,32740/1:111,117:228:99:3060,0,2641

document location: summary/5_ComplexDisease/*.snp.De_novo.tformat.GeneInfo.Filter.GO.KEGG.Gene.xlsx


Number of de novo variants:

GeneIndelSNP
LIG401
BMP401
LRFN401
AMER201
C1GALT1C101
KRTAP4-1202
FAM181B02
SLC35G601
C12orf6801
SRRM201
MGAT101
FLRT301
PNMA201
GCNT101
ZBTB4201
KRTAP1-501
SLITRK301
KRTAP11-101
PRPS1L101
SLC35G301
COL8A201
PRNP01
OR4M102
KRTAP17-110
RNF18302
ALDH1B101
ITPRIPL201
CHST1202
DDN01
KRTAP3-202
FUT201
HOXD1101
HDHD301
HNRNPCL102
KRTAP1-101
KLF1403
MAP1A01
OR10H101
ZNF35801
GJA301
KIF4B02
TACSTD201
GPR18201
TRIM5601
CLDN2301
KBTBD1301
GJB202
FAM46C01
ZBED610
P2RY402
LDHAL6B01
CTXN301
KRTAP1-301
GPR8401
CNR201
RPRML01
FOXE301
TMEM12110
LINGO301
FAM200B01
CHST601
SPPL2C01
GPR10101
TMEM8801
KDM6B01
OR10AD102
ITPRIPL101
NRIP101
FNDC901
PPAPDC201
SP901

document location: summary/5_ComplexDisease/GeneDenovoNum.xlsx


4.8 Mutation rate


In genetics, the mutation rate is the frequency of de novo mutations in a single gene or organism over a various amount of time. Mutation rates are not constant and are not limited to a single type of mutation, therefore there are many different types of mutations. Mutation rates are given for specific classes of mutations. Point mutations, are a class of mutations, which are small or large scale insertions or deletions. There are also Missense and Nonsense mutations, which are variations of point mutations. The rate of these types of substitutions can be further subdivided into a mutation spectrum which describes the influence of the genetic context on the mutation rate.

There are several natural units of time for each of these rates, with rates being characterized either as mutations per base pair per cell division, per gene per generation, or per genome per generation. The mutation rate of an organism is an evolved characteristic and is strongly influenced by the genetics of each organism, in addition to strong influence from the environment. The upper and lower limits to which mutation rates can evolve is the subject of ongoing investigation. However, the mutation rate does vary over the genome. Over DNA, RNA or a single gene mutation rates are changing.

When the mutation rate in humans increases certain health risks can occur, for example, cancer and other hereditary diseases. Having knowledge of mutation rates is vital to understanding the future of cancers and many hereditary diseases.


GeneChromosomeCCDSRegionDenovoNumMutationRatespvalueSignificance
TMC6chr17CCDS32748410.000***
ZSCAN31chr6CCDS4649,CCDS5900150.000***
EFCAB6chr22CCDS14050,CCDS14049380.000***
NEK11chr3CCDS54639,CCDS46915,CCDS3069250.000.00***
AP1B1chr22CCDS13855,CCDS54515,CCDS13856120.000.00***
CNTNAP4chr16CCDS10924440.000***
FAM73Bchr9CCDS691720.000.00***
MEGF10chr5CCDS4142290.000***
EFTUD2chr17CCDS11489,CCDS59295,CCDS45707240.000***
TMUB2chr17CCDS54134,CCDS11479110.000***
GJA3chr13CCDS928990.000***
AJAP1chr1CCDS5490.000***
APOPT1chr14CCDS998330.000.00***
ITPRIPL1chr2CCDS46360,CCDS33250,CCDS5437850.000.00***
DUOXA1chr15CCDS10119,CCDS61619,CCDS61620,CCDS6162120.000.00**
ST7Lchr1CCDS850,CCDS848,CCDS849,CCDS85240.000***
FOXRED2chr22CCDS1392950.000***
KRTAP29-1chr17CCDS62183210.010***
SEC31Bchr10CCDS7495240.000***
AHCTF1chr1CCDS162960.000.00***
MROchr18CCDS11947,CCDS45867,CCDS45869,CCDS45868200.000.00***
KAZNchr1CCDS152,CCDS41267,CCDS30604,CCDS41268240.000***
PLEKHA4chr19CCDS54291,CCDS1273730.000.00***
TREM1chr6CCDS4854,CCDS56427,CCDS5949920.000.00***
GANABchr11CCDS41656,CCDS8026,CCDS60818,CCDS6081780.000***
NECAB1chr8CCDS4788990.000***
STAG3chr7CCDS34703,CCDS64730210.000***
DPEP1chr16CCDS1098220.000.00***
OR6C68chr12CCDS31826160.010***
GREB1chr2CCDS42655,CCDS33147,CCDS33146470.000***
OBSCNchr1CCDS1570,CCDS59204,CCDS5806514900.000***
SNAPC2chr19CCDS1219040.000.00***
TTBK2chr15CCDS4202990.000***
CC2D1Achr19CCDS4251260.000***
CLDN7chr17CCDS11096,CCDS5408170.000.00***
SYNJ2chr6CCDS5254160.000***
AMACRchr5CCDS3902,CCDS3903,CCDS54836180.000***
CCDC67chr11CCDS44707660.000.00***
OR6K6chr1CCDS3090440.000.00***
PALMchr19CCDS32858,CCDS32857220.000***
OR2D3chr11CCDS31417100.010***
TEKT2chr1CCDS401160.000***
LBPchr20CCDS13304350.000.00***
TRAK2chr2CCDS234790.000***
YIPF1chr1CCDS58450.000***
ANKRD33chr12CCDS8815,CCDS44892280.000***
FAM53Achr4CCDS33939210.000.00***
ANKMY2chr7CCDS5361170.000***
CEP128chr14CCDS3213050.000***
LTKchr15CCDS10078,CCDS10077,CCDS4523790.000***
ATP5Bchr12CCDS892420.000.00***
MICBchr6CCDS43449720.000***
PUS7Lchr12CCDS8743,CCDS6110470.000***
HLA-Cchr6CCDS3439310280.180***
TGM2chr20CCDS13302250.000***
ZMYND12chr1CCDS467,CCDS5330550.000***
KRTAP10-2chr21CCDS42955240.020***
EGFchr4CCDS54795,CCDS3689,CCDS54794920.000.00***
FHDC1chr4CCDS34081190.000***
SCOCchr4CCDS3750,CCDS54806,CCDS5480770.000.00***
SLC12A7chr5CCDS34129390.000.00***
IL17REchr3CCDS2589,CCDS54552160.000***
PNPLA6chr19CCDS32891,CCDS54207,CCDS54206,CCDS59343360.000***
MYH7Bchr20CCDS42869410.000.00***
VWA2chr10CCDS758980.000.00***
FAM196Achr10CCDS31312120.000.00***
WDR60chr7CCDS47757340.000***
CPAMD8chr19CCDS42519640.000.00***
PRAMEchr22CCDS1380150.000***
FAM46Cchr1CCDS89630.000.00***
EYSchr6CCDS47445,CCDS47446,CCDS4967660.000***
FRMPD1chr9CCDS6612540.000***
PLEKHG5chr1CCDS41240,CCDS57967,CCDS79,CCDS41241,CCDS57969,CCDS5796850.000***
MYLKchr3CCDS3023,CCDS46897,CCDS58849,CCDS43141,CCDS46896540.000.00***
C1orf106chr1CCDS4429240.000.00***
PRAMEF12chr1CCDS41254480.010***
DCHS2chr4CCDS3785,CCDS47150,CCDS471513560.000***
MS4A14chr11CCDS31569,CCDS41652,CCDS58136420.000.00***
ABCB11chr2CCDS46444280.000.00***
CLEC4Fchr2CCDS1910100.000***
NEU4chr2CCDS54442,CCDS2553,CCDS54441110.000***
KRTAP9-3chr17CCDS1138570.010***
DNMT1chr19CCDS12228,CCDS45958680.000***
POLNchr4CCDS3360680.000***
EME2chr16CCDS58404130.000.00***
LAD1chr1CCDS1410120.000***
FSD2chr15CCDS45332,CCDS6173830.000.00***
MTMR7chr8CCDS34851400.000***
ART5chr11CCDS7743180.000***
COG6chr13CCDS45042,CCDS9370400.000***
ACER1chr19CCDS1216140.000***
OR52I2chr11CCDS3135550.000.00***
PLCB2chr15CCDS42020,CCDS61592,CCDS61591550.000***
ADPRHL1chr13CCDS9536,CCDS953530.000.00***
SYNPOchr5CCDS54937,CCDS4308,CCDS5493860.000.00***
DPYSL2chr8CCDS59096,CCDS605190.000***
CEP89chr19CCDS32987620.000***
SFI1chr22CCDS43005,CCDS58804,CCDS43004,CCDS58803240.000***
OCA2chr15CCDS10020430.000***
SEC14L6chr22CCDS54518150.000***

document location: summary/5_ComplexDisease/geneMutRate_p_Filtered.xlsx



5. Contact us


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