rs132630317
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001399.5(EDA):c.1045G>A(p.Ala349Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. A349S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001399.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1045G>A | p.Ala349Thr | missense_variant | 8/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.1045G>A | p.Ala349Thr | missense_variant | 8/8 | 1 | NM_001399.5 | P4 | |
EDA | ENST00000374553.6 | c.1039G>A | p.Ala347Thr | missense_variant | 8/8 | 1 | A1 | ||
EDA | ENST00000524573.5 | c.1030G>A | p.Ala344Thr | missense_variant | 8/8 | 1 | A1 | ||
EDA | ENST00000616899.1 | c.649G>A | p.Ala217Thr | missense_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1098180Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363536
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 349 of the EDA protein (p.Ala349Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 9683615, 15461765). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11040). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2023 | 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: 11343303, 18666859, 21457804, 30192988, 15461765, 35131284, 22446708, 22566850, 30117778, 31129666, 24312213, 11295832, 9683615, 34863015, 26582918, 24077912) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at