rs1556110308

chrX-70035403-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001399.5(EDA):c.970G>A(p.Val324Met) 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 (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.34

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant X-70035403-G-A is Pathogenic according to our data. Variant chrX-70035403-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 458662.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.970G>A	p.Val324Met	missense_variant	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.970G>A	p.Val324Met	missense_variant	8/8	1	NM_001399.5	P4
EDA	ENST00000374553.6	c.964G>A	p.Val322Met	missense_variant	8/8	1		A1
EDA	ENST00000524573.5	c.955G>A	p.Val319Met	missense_variant	8/8	1		A1
EDA	ENST00000616899.1	c.574G>A	p.Val192Met	missense_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 324 of the EDA protein (p.Val324Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ectodermal dysplasia (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458662). 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 with a positive predictive value of 95%. This variant disrupts the p.Val324 amino acid residue in EDA. Other variant(s) that disrupt this residue have been observed in individuals with EDA-related conditions (PMID: 23989902), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.5	N;N;N;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.64
MutPred		0.54		.;Gain of sheet (P = 0.0827);.;.;
MVP		0.99
MPC		1.9
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556110308; hg19: chrX-69255253;