rs886039347
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_001399.5(EDA):c.1069C>T(p.Arg357Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,191 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. R357P) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.1069C>T | p.Arg357Trp | missense_variant | 8/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.1069C>T | p.Arg357Trp | missense_variant | 8/8 | 1 | NM_001399.5 | P4 | |
EDA | ENST00000374553.6 | c.1063C>T | p.Arg355Trp | missense_variant | 8/8 | 1 | A1 | ||
EDA | ENST00000524573.5 | c.1054C>T | p.Arg352Trp | missense_variant | 8/8 | 1 | A1 | ||
EDA | ENST00000616899.1 | c.673C>T | p.Arg225Trp | missense_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1098191Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1AN XY: 363545
GnomAD4 genome ? Cov.: 21
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | EDA: PM1, PM2, PM5, PS4:Moderate - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Apr 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2022 | Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23991204, 28045201) - |
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 357 of the EDA protein (p.Arg357Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of X-linked hypohidrotic ectodermal dysplasia (PMID: 28045201, 31796081; Invitae). ClinVar contains an entry for this variant (Variation ID: 265112). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jul 17, 2019 | ACMG categories: PM1,PM2,PP1,PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at