rs879255551
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001399.5(EDA):c.865C>T(p.Arg289Cys) 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. R289P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001399.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.865C>T | p.Arg289Cys | missense_variant | 7/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.865C>T | p.Arg289Cys | missense_variant | 7/8 | 1 | NM_001399.5 | P4 | |
EDA | ENST00000374553.6 | c.865C>T | p.Arg289Cys | missense_variant | 7/8 | 1 | A1 | ||
EDA | ENST00000524573.5 | c.856C>T | p.Arg286Cys | missense_variant | 7/8 | 1 | A1 | ||
EDA | ENST00000616899.1 | c.469C>T | p.Arg157Cys | missense_variant | 6/7 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2022 | Experimental studies have shown that this missense change affects EDA function (PMID: 27144394). 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 EDA protein function. ClinVar contains an entry for this variant (Variation ID: 253054). This missense change has been observed in individuals with non-syndromic oligodontia (PMID: 19278982; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 289 of the EDA protein (p.Arg289Cys). This variant disrupts the p.Arg289 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26753551; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Medical Molecular Genetics Department, National Research Center | Feb 13, 2021 | - - |
Tooth agenesis, selective, X-linked, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 17, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at