X-70035500-C-T

Position:

• chrX-70035500-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_001399.5(EDA):​c.1067C>T​(p.Ala356Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A356D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.29

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant X-70035500-C-T is Pathogenic according to our data. Variant chrX-70035500-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70035500-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.1067C>T	p.Ala356Val	missense_variant	8/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.1067C>T	p.Ala356Val	missense_variant	8/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.1061C>T	p.Ala354Val	missense_variant	8/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.1052C>T	p.Ala351Val	missense_variant	8/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.671C>T	p.Ala224Val	missense_variant	7/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2018	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala356 amino acid residue in EDA. Other variant(s) that disrupt this residue have been observed in individuals with EDA-related conditions (PMID: 9683615, 11279189), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with hypohidrotic ectodermal dysplasia (PMID: 20979233). ClinVar contains an entry for this variant (Variation ID: 228255). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 356 of the EDA protein (p.Ala356Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2015	The p.Ala356Val variant in EDA has been reported in 2 individuals with clinical features of X-linked hypohidrotic ectodermaldysplasia (XLHED)(Clauss 2010, Cluze au 2011) and was absent from large population studies. In addition, a different amino acid change at the same position (p.Ala356Asn) has been identified in 1 ma le with XLHED suggesting that a change at this position may not be tolerated (Mo nreal 2008). Computational prediction tools and conservation analysis suggest th at the p.Ala356Val variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala356V al variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	.;D;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.3	.;L;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N;N;N;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.59
MutPred		0.70		.;Gain of methylation at K355 (P = 0.0379);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.96
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: rs876657639; hg19: chrX-69255350;