1-34784856-C-T
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_024009.3(GJB3):c.94C>T(p.Arg32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,614,166 control chromosomes in the GnomAD database, including 759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.021 ( 51 hom., cov: 32)
Exomes 𝑓: 0.030 ( 708 hom. )
Consequence
GJB3
NM_024009.3 missense
NM_024009.3 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 1.13
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 -18 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_024009.3
BP4
Computational evidence support a benign effect (MetaRNN=0.010469735).
BP6
Variant 1-34784856-C-T is Benign according to our data. Variant chr1-34784856-C-T is described in ClinVar as [Benign]. Clinvar id is 46088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34784856-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3221/152286) while in subpopulation NFE AF= 0.0311 (2117/68024). AF 95% confidence interval is 0.03. There are 51 homozygotes in gnomad4. There are 1605 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 3221 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB3 | NM_024009.3 | c.94C>T | p.Arg32Trp | missense_variant | 2/2 | ENST00000373366.3 | NP_076872.1 | |
GJB3 | NM_001005752.2 | c.94C>T | p.Arg32Trp | missense_variant | 2/2 | NP_001005752.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB3 | ENST00000373366.3 | c.94C>T | p.Arg32Trp | missense_variant | 2/2 | 1 | NM_024009.3 | ENSP00000362464.2 | ||
GJB3 | ENST00000373362.3 | c.94C>T | p.Arg32Trp | missense_variant | 2/2 | 1 | ENSP00000362460.3 | |||
SMIM12 | ENST00000426886.1 | n.208-66447G>A | intron_variant | 1 | ENSP00000429902.1 | |||||
ENSG00000255811 | ENST00000542839.1 | n.110+3132G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0212 AC: 3224AN: 152168Hom.: 52 Cov.: 32
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GnomAD3 exomes AF: 0.0234 AC: 5877AN: 251420Hom.: 95 AF XY: 0.0239 AC XY: 3246AN XY: 135892
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GnomAD4 exome AF: 0.0297 AC: 43378AN: 1461880Hom.: 708 Cov.: 33 AF XY: 0.0293 AC XY: 21333AN XY: 727236
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GnomAD4 genome AF: 0.0212 AC: 3221AN: 152286Hom.: 51 Cov.: 32 AF XY: 0.0216 AC XY: 1605AN XY: 74450
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ClinVar
Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:6
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | GJB3: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 25262649, 11175305, 12702148, 12165562, 24498627, 20981092, 10757647, 27884173, 10888284, 30245029, 29318123) - |
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Arg32Trp in Exon 02 of GJB3: This variant is not expected to have clinical signi ficance because it has been identified in 3.0% (211/7020) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs1805063). - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 07, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Erythrokeratodermia variabilis et progressiva 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
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
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
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