rs121908450
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_022336.4(EDAR):c.266G>A(p.Arg89His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,084 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89C) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDAR | NM_022336.4 | c.266G>A | p.Arg89His | missense_variant | 4/12 | ENST00000258443.7 | |
EDAR | XM_006712204.2 | c.266G>A | p.Arg89His | missense_variant | 4/11 | ||
RANBP2 | XM_047445367.1 | c.8370+156242C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDAR | ENST00000258443.7 | c.266G>A | p.Arg89His | missense_variant | 4/12 | 1 | NM_022336.4 | P1 | |
EDAR | ENST00000376651.1 | c.266G>A | p.Arg89His | missense_variant | 4/11 | 2 | |||
EDAR | ENST00000409271.5 | c.266G>A | p.Arg89His | missense_variant | 5/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251332Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135890
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 19, 2018 | - - |
Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
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 | Dec 30, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 89 of the EDAR protein (p.Arg89His). This variant is present in population databases (rs121908450, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive hypohidrotic ectodermal dysplasia and/or mild autosomal dominant ectodermal dysplasia (PMID: 18231121, 20236127, 20979233). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5849). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EDAR protein function. This variant disrupts the p.Arg89 amino acid residue in EDAR. Other variant(s) that disrupt this residue have been determined to be pathogenic (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. - |
Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Hehr Laboratory, Center for Human Genetics Regensburg | Oct 09, 2016 | - - |
Ectodermal dysplasia 10a, hypohidrotic/hair/tooth type, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at