rs1554200995
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000165.5(GJA1):c.140A>T(p.Asp47Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D47H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000165.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.140A>T | p.Asp47Val | missense_variant | 2/2 | ENST00000282561.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.140A>T | p.Asp47Val | missense_variant | 2/2 | 1 | NM_000165.5 | P1 | |
GJA1 | ENST00000647564.1 | c.140A>T | p.Asp47Val | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000649003.1 | c.140A>T | p.Asp47Val | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000650427.1 | c.140A>T | p.Asp47Val | missense_variant | 2/2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2018 | - - |
Oculodentodigital dysplasia, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 02, 2017 | For these reasons, this variant has been classified as Pathogenic. Several different missense substitution at this codon (p.Asp47) in the paralogous gene GJA8 have been determined to be pathogenic (PMID: 26004348, 27216975). This suggests that the aspartic acid residue is critical for GJA1 protein function and that other missense substitutions at this position may also be pathogenic, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GJA1-related disease. This sequence change replaces aspartic acid with valine at codon 47 of the GJA1 protein (p.Asp47Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant has been shown to arise de novo in an individual affected with a GJA1-related condition (Invitae). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at