rs1554201018
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The ENST00000282561.4(GJA1):c.412G>A(p.Gly138Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G138D) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000282561.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.412G>A | p.Gly138Ser | missense_variant | 2/2 | ENST00000282561.4 | NP_000156.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.412G>A | p.Gly138Ser | missense_variant | 2/2 | 1 | NM_000165.5 | ENSP00000282561 | P1 | |
GJA1 | ENST00000647564.1 | c.412G>A | p.Gly138Ser | missense_variant | 2/2 | ENSP00000497565 | P1 | |||
GJA1 | ENST00000649003.1 | c.412G>A | p.Gly138Ser | missense_variant | 2/2 | ENSP00000497283 | P1 | |||
GJA1 | ENST00000650427.1 | c.412G>A | p.Gly138Ser | missense_variant | 2/2 | ENSP00000497367 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Oculodentodigital dysplasia, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly138 amino acid residue in GJA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19338053, 18003637, 27226478, 18946008, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with autosomal dominant oculodentodigital dysplasia (PMID: 18946008, 25388818, 19338053). ClinVar contains an entry for this variant (Variation ID: 537756). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 138 of the GJA1 protein (p.Gly138Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at