rs1555339539
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_021954.4(GJA3):c.82G>A(p.Val28Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,568 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V28V) has been classified as Likely benign.
Frequency
Consequence
NM_021954.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA3 | NM_021954.4 | c.82G>A | p.Val28Met | missense_variant | 2/2 | ENST00000241125.4 | |
GJA3 | XM_011535048.3 | c.82G>A | p.Val28Met | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA3 | ENST00000241125.4 | c.82G>A | p.Val28Met | missense_variant | 2/2 | 3 | NM_021954.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 7.00e-7 AC: 1AN: 1429568Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 706420
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cataract 14 multiple types Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | 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 not expected to disrupt GJA3 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val28 amino acid residue in GJA3. Other variant(s) that disrupt this residue have been observed in individuals with GJA3-related conditions (PMID: 32384692), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 468544). This missense change has been observed in individuals with clinical features of autosomal dominant congenital cataract (PMID: 16254549; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 28 of the GJA3 protein (p.Val28Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at