rs74315315
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM5PP3_ModeratePP5_ModerateBS2_Supporting
The NM_024009.3(GJB3):c.34G>A(p.Gly12Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,048 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12R) has been classified as Pathogenic.
Frequency
Consequence
NM_024009.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB3 | NM_024009.3 | c.34G>A | p.Gly12Ser | missense_variant | 2/2 | ENST00000373366.3 | |
GJB3 | NM_001005752.2 | c.34G>A | p.Gly12Ser | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB3 | ENST00000373366.3 | c.34G>A | p.Gly12Ser | missense_variant | 2/2 | 1 | NM_024009.3 | P1 | |
GJB3 | ENST00000373362.3 | c.34G>A | p.Gly12Ser | missense_variant | 2/2 | 1 | P1 | ||
SMIM12 | ENST00000426886.1 | c.208-66387C>T | intron_variant, NMD_transcript_variant | 1 | |||||
ENST00000542839.1 | n.110+3192C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251314Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135820
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727240
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 30, 2023 | This variant is present in population databases (rs74315315, gnomAD 0.03%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB3 protein function. This missense change has been observed in individual(s) with autosomal recessive erythrokeratodermia variabilis (PMID: 29992552). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the GJB3 protein (p.Gly12Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at