1-34785291-T-G
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_024009.3(GJB3):āc.529T>Gā(p.Tyr177Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,054 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0055 ( 2 hom., cov: 32)
Exomes š: 0.00062 ( 5 hom. )
Consequence
GJB3
NM_024009.3 missense
NM_024009.3 missense
Scores
8
7
3
Clinical Significance
Conservation
PhyloP100: 7.97
Genes affected
GJB3 (HGNC:4285): (gap junction protein beta 3) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]
SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
PM1
In a chain Gap junction beta-3 protein (size 269) in uniprot entity CXB3_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_024009.3
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.017602742).
BP6
Variant 1-34785291-T-G is Benign according to our data. Variant chr1-34785291-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 178352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00553 (839/151692) while in subpopulation AFR AF= 0.0192 (796/41360). AF 95% confidence interval is 0.0181. There are 2 homozygotes in gnomad4. There are 379 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 839 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB3 | NM_024009.3 | c.529T>G | p.Tyr177Asp | missense_variant | 2/2 | ENST00000373366.3 | NP_076872.1 | |
GJB3 | NM_001005752.2 | c.529T>G | p.Tyr177Asp | missense_variant | 2/2 | NP_001005752.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB3 | ENST00000373366.3 | c.529T>G | p.Tyr177Asp | missense_variant | 2/2 | 1 | NM_024009.3 | ENSP00000362464 | P1 | |
GJB3 | ENST00000373362.3 | c.529T>G | p.Tyr177Asp | missense_variant | 2/2 | 1 | ENSP00000362460 | P1 | ||
SMIM12 | ENST00000426886.1 | c.208-66882A>C | intron_variant, NMD_transcript_variant | 1 | ENSP00000429902 | |||||
ENST00000542839.1 | n.110+2697A>C | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00554 AC: 839AN: 151574Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00141 AC: 355AN: 251182Hom.: 1 AF XY: 0.000972 AC XY: 132AN XY: 135798
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GnomAD4 exome AF: 0.000617 AC: 902AN: 1461362Hom.: 5 Cov.: 33 AF XY: 0.000514 AC XY: 374AN XY: 727034
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GnomAD4 genome AF: 0.00553 AC: 839AN: 151692Hom.: 2 Cov.: 32 AF XY: 0.00511 AC XY: 379AN XY: 74112
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 25, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2019 | This variant is associated with the following publications: (PMID: 18809214, 25262649, 20981092, 15131355, 30245029) - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Tyr177Asp in Exon 02 of GJB3: This variant is not expected to have clinical sign ificance because it has been identified in 1.8% (67/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs80297119). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 31, 2016 | - - |
Erythrokeratodermia variabilis et progressiva 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at