rs727503010
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_001399.5(EDA):c.948delC(p.Phe317fs) 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 (★).
Frequency
Genomes: not found (cov: 21)
Consequence
EDA
NM_001399.5 frameshift
NM_001399.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.46
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-70035380-AC-A is Pathogenic according to our data. Variant chrX-70035380-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 163323.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.948delC | p.Phe317fs | frameshift_variant | 8/8 | ENST00000374552.9 | NP_001390.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.948delC | p.Phe317fs | frameshift_variant | 8/8 | 1 | NM_001399.5 | ENSP00000363680.4 | ||
EDA | ENST00000374553.6 | c.942delC | p.Phe315fs | frameshift_variant | 8/8 | 1 | ENSP00000363681.2 | |||
EDA | ENST00000524573.5 | c.933delC | p.Phe312fs | frameshift_variant | 8/8 | 1 | ENSP00000432585.1 | |||
EDA | ENST00000616899.1 | c.552delC | p.Phe185fs | frameshift_variant | 7/7 | 5 | ENSP00000481963.1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2014 | The p.Phe317fs variant in EDA has not been previously reported in individuals or any other families with clinical features of X-linked hypohidrotic extodermal d ysplasia (XLHED) and was absent from large population studies. This variant is p redicted to cause a frameshift, which alters the protein?s amino acid sequence b eginning at position 317 and leads to a premature termination codon 57 amino aci ds downstream. This alteration is then predicted to lead to a truncated or absen t protein. Heterozygous loss of function of function of the EDA gene is an estab lished disease mechanism in XLHED. In summary, this variant meets our criteria t o be classified as pathogenic for XLHED in an X-linked manner (http://www.partne rs.org/personalizedmedicine/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at