rs879255551

Positions:

• chrX-70033469-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000374552.9(EDA):​c.865C>T​(p.Arg289Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R289P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA ENST00000374552.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000374552.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70033470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-70033469-C-T is Pathogenic according to our data. Variant chrX-70033469-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 253054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.865C>T	p.Arg289Cys	missense_variant	7/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.865C>T	p.Arg289Cys	missense_variant	7/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.865C>T	p.Arg289Cys	missense_variant	7/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.856C>T	p.Arg286Cys	missense_variant	7/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.469C>T	p.Arg157Cys	missense_variant	6/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Medical Molecular Genetics Department, National Research Center	Feb 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2022	Experimental studies have shown that this missense change affects EDA function (PMID: 27144394). 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: 253054). This missense change has been observed in individuals with non-syndromic oligodontia (PMID: 19278982; Invitae). 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 289 of the EDA protein (p.Arg289Cys). This variant disrupts the p.Arg289 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26753551; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Tooth agenesis, selective, X-linked, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 17, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.89
MutPred		0.91		Gain of catalytic residue at P288 (P = 0.0135);Gain of catalytic residue at P288 (P = 0.0135);.;.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255551; hg19: chrX-69253319; COSMIC: COSV65779757; COSMIC: COSV65779757;