rs727503007
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001399.5(EDA):c.676C>T(p.Gln226Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 21)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
EDA
NM_001399.5 stop_gained
NM_001399.5 stop_gained
Scores
3
1
1
Clinical Significance
Conservation
PhyloP100: 5.64
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-70028006-C-T is Pathogenic according to our data. Variant chrX-70028006-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 163315.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.676C>T | p.Gln226Ter | stop_gained | 4/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.676C>T | p.Gln226Ter | stop_gained | 4/8 | 1 | NM_001399.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1085397Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 354129
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1085397
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30
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0
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354129
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 21, 2014 | The Gln226X variant in EDA has not been previously reported in individuals with hyophidrotic ectodermal dysplasia. Data from large population studies is insuffi cient to assess the frequency of this variant. This nonsense variant leads to a premature termination codon at position 226, which is predicted to lead to a tru ncated or absent protein. Heterozygous loss of function of the EDA gene is an es tablished disease mechanism in XLHED. In summary, this variant meets our criter ia to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2019 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln226*) in the EDA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EDA-related conditions. ClinVar contains an entry for this variant (Variation ID: 163315). Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at