chr1-34785300-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_StrongBS2_Supporting
The NM_024009.3(GJB3):c.538C>T(p.Arg180Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
GJB3
NM_024009.3 stop_gained
NM_024009.3 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.00
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 Uncertain_significance. Variant got 3 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
BS2
High AC in GnomAd4 at 6 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB3 | NM_024009.3 | c.538C>T | p.Arg180Ter | stop_gained | 2/2 | ENST00000373366.3 | |
GJB3 | NM_001005752.2 | c.538C>T | p.Arg180Ter | stop_gained | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB3 | ENST00000373366.3 | c.538C>T | p.Arg180Ter | stop_gained | 2/2 | 1 | NM_024009.3 | P1 | |
GJB3 | ENST00000373362.3 | c.538C>T | p.Arg180Ter | stop_gained | 2/2 | 1 | P1 | ||
SMIM12 | ENST00000426886.1 | c.208-66891G>A | intron_variant, NMD_transcript_variant | 1 | |||||
ENST00000542839.1 | n.110+2688G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151842Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251074Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135724
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461202Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 726936
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74268
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this premature translational stop signal affects GJB3 function (PMID: 16077902, 21204020). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 6486). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 9843210, 29106878, 31564438, 32645618). This variant is present in population databases (rs74315319, gnomAD 0.1%). This sequence change creates a premature translational stop signal (p.Arg180*) in the GJB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the GJB3 protein. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2021 | Observed in the heterozygous state in patients with hearing loss (Xia et al., 1998; Chen et al., 2011; Yao et al., 2013; Li et al., 2015; Liu et al., 2016); Reported in multiple individuals without hearing loss or to not differ in frequency between patients with hearing loss and control populations (Yin et al., 2013; Huang et al., 2017; Dai et al., 2019); Nonsense variant predicted to result in protein truncation as the last 91 amino acids are lost, although pathogenic loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 28604950, 19197336, 30245029, 30896630, 21204020, 9843210, 31564438, 16077902, 30589569, 27176802, 23638949, 25262649, 29106878, 31541171, 30235673, 26330914, 23718755, 21917135, 27727359, 28505178) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 04, 2020 | - - |
Autosomal dominant nonsyndromic hearing loss 2B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1998 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2013 | The Arg180X variant in GJB3 has been reported in two individuals with hearing lo ss (Xia 1998, Yao 2013). This variant was shown to segregate in one individual w ith hearing loss but was also seen in one unaffected family member (Xia 1998). This nonsense variant leads to a premature termination codon at position 180 and the variant has been shown to impact protein function (He 2005). However, evide nce is lacking for a clear association of the GJB3 gene with hearing loss in eit her a recessive or dominant manner. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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