X-70033430-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001399.5(EDA):​c.826C>T​(p.Arg276Cys) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

EDA
NM_001399.5 missense

Scores

8
6
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.85
Variant links:
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.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001399.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-70033431-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant X-70033430-C-T is Pathogenic according to our data. Variant chrX-70033430-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70033430-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDANM_001399.5 linkc.826C>T p.Arg276Cys missense_variant Exon 7 of 8 ENST00000374552.9 NP_001390.1 Q92838-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDAENST00000374552.9 linkc.826C>T p.Arg276Cys missense_variant Exon 7 of 8 1 NM_001399.5 ENSP00000363680.4 Q92838-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2
Feb 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg276 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 31908). This missense change has been observed in individuals with clinical features of, or diagnosis of, ectodermal dysplasia (PMID: 19921643, 21357618; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 276 of the EDA protein (p.Arg276Cys). -

Dec 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Ectodermal dysplasia Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Apr 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

EDA: PM1, PM2, PS4:Moderate, PP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.62
.;D;.;.
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Benign
0.0
N;N;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-2.1
N;N;N;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0010
D;.;.;.
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.73
MutPred
0.84
Loss of MoRF binding (P = 0.0045);Loss of MoRF binding (P = 0.0045);.;.;
MVP
1.0
MPC
2.2
ClinPred
0.93
D
GERP RS
5.5
Varity_R
0.89
gMVP
0.94

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387907197; hg19: chrX-69253280; COSMIC: COSV101000009; COSMIC: COSV101000009; API