rs144964568
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_024009.3(GJB3):c.703C>T(p.Arg235*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,702 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024009.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB3 | NM_024009.3 | c.703C>T | p.Arg235* | stop_gained | Exon 2 of 2 | ENST00000373366.3 | NP_076872.1 | |
GJB3 | NM_001005752.2 | c.703C>T | p.Arg235* | stop_gained | Exon 2 of 2 | NP_001005752.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB3 | ENST00000373366.3 | c.703C>T | p.Arg235* | stop_gained | Exon 2 of 2 | 1 | NM_024009.3 | ENSP00000362464.2 | ||
GJB3 | ENST00000373362.3 | c.703C>T | p.Arg235* | stop_gained | Exon 2 of 2 | 1 | ENSP00000362460.3 | |||
SMIM12 | ENST00000426886.1 | n.208-67056G>A | intron_variant | Intron 2 of 4 | 1 | ENSP00000429902.1 | ||||
ENSG00000255811 | ENST00000542839.1 | n.110+2523G>A | intron_variant | Intron 1 of 1 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249780Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135362
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461554Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18AN XY: 727058
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Nonsyndromic Deafness Pathogenic:1
This variant creates a premature stop signal at position 235 of the GJB3 protein, written as p.Arg235Ter or p.R235*. The substitution is predicted to result in a non-functional GJB3 protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the ClinVar Database (NCBI National Library of Medicine, NIH), but it has been described in 3 alleles out of 119888, in the ExAC database, all of them belonging to heterozygous carries of European origin. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant. -
not provided Uncertain:1
This sequence change creates a premature translational stop signal (p.Arg235*) in the GJB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the GJB3 protein. This variant is present in population databases (rs144964568, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GJB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 561271). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at