rs1556039088
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate
The NM_001399.5(EDA):c.479G>A(p.Ser160Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S160R) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 22)
Consequence
EDA
NM_001399.5 missense
NM_001399.5 missense
Scores
1
5
10
Clinical Significance
Conservation
PhyloP100: 5.55
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 6 ACMG points.
PM1
?
In a chain Ectodysplasin-A, secreted form (size 231) in uniprot entity EDA_HUMAN there are 151 pathogenic changes around while only 13 benign (92%) in NM_001399.5
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-69957109-G-A is Pathogenic according to our data. Variant chrX-69957109-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 458657.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDA | NM_001399.5 | c.479G>A | p.Ser160Asn | missense_variant | 2/8 | ENST00000374552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDA | ENST00000374552.9 | c.479G>A | p.Ser160Asn | missense_variant | 2/8 | 1 | NM_001399.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
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 | Invitae | Mar 09, 2021 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. This variant has been observed in individual(s) with clinical features of hypohidrotic ectodermal dysplasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 458657). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 160 of the EDA protein (p.Ser160Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;N;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;.
REVEL
Benign
Sift
Benign
T;.;.;T;.
Sift4G
Benign
T;T;T;T;T
Polyphen
D;D;D;.;.
Vest4
MutPred
Loss of phosphorylation at S160 (P = 0.0073);Loss of phosphorylation at S160 (P = 0.0073);Loss of phosphorylation at S160 (P = 0.0073);.;.;
MVP
MPC
1.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at