rs557166582
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_022336.4(EDAR):c.292C>T(p.Arg98Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R98Q) has been classified as Pathogenic.
Frequency
Consequence
NM_022336.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDAR | NM_022336.4 | c.292C>T | p.Arg98Trp | missense_variant | 4/12 | ENST00000258443.7 | |
EDAR | XM_006712204.2 | c.292C>T | p.Arg98Trp | missense_variant | 4/11 | ||
RANBP2 | XM_047445367.1 | c.8370+156216G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDAR | ENST00000258443.7 | c.292C>T | p.Arg98Trp | missense_variant | 4/12 | 1 | NM_022336.4 | P1 | |
EDAR | ENST00000376651.1 | c.292C>T | p.Arg98Trp | missense_variant | 4/11 | 2 | |||
EDAR | ENST00000409271.5 | c.292C>T | p.Arg98Trp | missense_variant | 5/12 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251288Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727210
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74506
ClinVar
Submissions by phenotype
Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 13, 2017 | This variant was identified as homozygous - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2019 | - - |
Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 98 of the EDAR protein (p.Arg98Trp). This variant is present in population databases (rs557166582, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ectodermal dysplasia (PMID: 22032522; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 532549). 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 EDAR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at