rs397516656
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001399.5(EDA):c.272dup(p.Ser91ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S91S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
EDA
NM_001399.5 frameshift
NM_001399.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.281
Genes affected
EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-69616579-A-AG is Pathogenic according to our data. Variant chrX-69616579-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 44187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.272dup | p.Ser91ArgfsTer9 | frameshift_variant | 1/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.272dup | p.Ser91ArgfsTer9 | frameshift_variant | 1/8 | 1 | NM_001399.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change creates a premature translational stop signal (p.Ser91Argfs*9) in the EDA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EDA-related conditions. ClinVar contains an entry for this variant (Variation ID: 44187). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 17, 2011 | The Ser91fs variant in EDA has not been reported in the literature nor previousl y identified by our laboratory. This frameshift variant is predicted to alter t he protein?s amino acid sequence beginning at position 91 and lead to a prematur e termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the E DA gene is an established disease mechanism in XLHED. In summary, this variant m eets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) . - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at