rs200055020
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_024009.3(GJB3):c.479G>A(p.Arg160His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160P) has been classified as Uncertain significance.
Frequency
Consequence
NM_024009.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB3 | NM_024009.3 | c.479G>A | p.Arg160His | missense_variant | 2/2 | ENST00000373366.3 | |
GJB3 | NM_001005752.2 | c.479G>A | p.Arg160His | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB3 | ENST00000373366.3 | c.479G>A | p.Arg160His | missense_variant | 2/2 | 1 | NM_024009.3 | P1 | |
GJB3 | ENST00000373362.3 | c.479G>A | p.Arg160His | missense_variant | 2/2 | 1 | P1 | ||
SMIM12 | ENST00000426886.1 | c.208-66832C>T | intron_variant, NMD_transcript_variant | 1 | |||||
ENST00000542839.1 | n.110+2747C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000526 AC: 80AN: 152024Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00159 AC: 399AN: 251364Hom.: 0 AF XY: 0.00136 AC XY: 185AN XY: 135890
GnomAD4 exome AF: 0.000807 AC: 1180AN: 1461734Hom.: 1 Cov.: 34 AF XY: 0.000788 AC XY: 573AN XY: 727192
GnomAD4 genome ? AF: 0.000526 AC: 80AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74384
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 30, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Has been observed at GeneDx in two unrelated individuals with hearing loss with pathogenic GJB2 variants - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 07, 2014 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg160His var iant in GJB3 has not been previously reported in individuals with hearing loss, but has been identified in 4/8600 European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/) and in 0.8% (1/128) of Mexican ancestry chromosomes by the 1000 Genomes Project (dbSNP rs200055020). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg160His var iant is uncertain, the frequency data suggest that it is more likely to be benig n. - |
GJB3-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 10, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Erythrokeratodermia variabilis et progressiva 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at