rs132630309
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001399.5(EDA):c.206G>T(p.Arg69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,210,205 control chromosomes in the GnomAD database, including 17 homozygotes. There are 1,824 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001399.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00302 AC: 339AN: 112284Hom.: 1 Cov.: 24 AF XY: 0.00258 AC XY: 89AN XY: 34438
GnomAD3 exomes AF: 0.00286 AC: 519AN: 181348Hom.: 1 AF XY: 0.00302 AC XY: 201AN XY: 66662
GnomAD4 exome AF: 0.00504 AC: 5529AN: 1097871Hom.: 16 Cov.: 32 AF XY: 0.00477 AC XY: 1735AN XY: 363367
GnomAD4 genome AF: 0.00301 AC: 338AN: 112334Hom.: 1 Cov.: 24 AF XY: 0.00258 AC XY: 89AN XY: 34500
ClinVar
Submissions by phenotype
not provided Benign:7
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This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092) -
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EDA: PP3, BS2 -
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2Uncertain:2Benign:2
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not specified Benign:3
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p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant in the same gene (Kere1996, Vincent 2001, Schneider 2011, Dietz 2013). However, this variant is not expected to have clinical significance because it has been identified in 0.5% (231/47072 ) of European chromosomes (94 hemizygotes) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs132630309). -
Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181348 control chromosomes in the gnomAD database, including 201 hemizygotes and 1 homozygote. The high occurrence of hemizygotes suggests that the variant is benign. Although the variant, c.206G>T, has been reported in the literature in individuals affected with Hypohidrotic Ectodermal Dysplasia or related phenotypes (e.g. Kere_1996, Vincent_2001, Stagi_2009, Schneider_2011, Dietz_2013, Bonds_2014, Burger_2014, Ferstl_2018), however, no evidence for cosegregation was reported. In addition, in some of these cases co-occurrences with other pathogenic variants have been reported, which could explain the phenotype (EDA c.991C>T (p.Gln331Ter), Dietz_2013; EDA c.467G>A (p.Arg156His), Stagi_2009; TP63 c.952C>T (p.Arg318Cys), Ferstl_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (n=1), uncertain significance (n=2), and benign (n=4) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -
EDA-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at