chrX-69616316-AC-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001399.5(EDA):c.11del(p.Pro4ArgfsTer53) 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: 24)
Consequence
EDA
NM_001399.5 frameshift
NM_001399.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.09
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 219 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-69616316-AC-A is Pathogenic according to our data. Variant chrX-69616316-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 817272.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.11del | p.Pro4ArgfsTer53 | frameshift_variant | 1/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.11del | p.Pro4ArgfsTer53 | frameshift_variant | 1/8 | 1 | NM_001399.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
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:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be disease-causing (ClinVar ID: VCV000817272). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2018 | The c.11delC variant in the EDA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.11delC variant causes a frameshift starting with codon Proline 4, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Pro4ArgfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11delC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.11delC as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at