rs886039347

Positions:

• chrX-70035502-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.1069C>T​(p.Arg357Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,191 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. R357P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.47

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, 0.824
• PP5: Variant X-70035502-C-T is Pathogenic according to our data. Variant chrX-70035502-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70035502-C-T is described in Lovd as [Pathogenic]. Variant chrX-70035502-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.1069C>T	p.Arg357Trp	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.1069C>T	p.Arg357Trp	missense_variant	8/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.1063C>T	p.Arg355Trp	missense_variant	8/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.1054C>T	p.Arg352Trp	missense_variant	8/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.673C>T	p.Arg225Trp	missense_variant	7/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098191 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363545

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2022	Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23991204, 28045201) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	EDA: PM1, PM2, PM5, PS4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Apr 22, 2021	- -

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 357 of the EDA protein (p.Arg357Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of X-linked hypohidrotic ectodermal dysplasia (PMID: 28045201, 31796081; Invitae). ClinVar contains an entry for this variant (Variation ID: 265112). 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%. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jul 17, 2019

ACMG categories: PM1,PM2,PP1,PP3 -

EDA-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

The EDA c.1069C>T variant is predicted to result in the amino acid substitution p.Arg357Trp. This variant has been reported in the hemizygous state in individuals with hypohidrotic ectodermal dysplasia (Arte et al. 2013. PubMed ID: 23991204; Monroy-Jaramillo et al. 2017. PubMed ID: 28045201; Martínez-Romero et al 2019. PubMed ID: 31796081). This variant has not been reported in a large population database, indicating this variant is rare and has been interpreted as pathogenic and likely pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/265112/). Additionally, a different missense change impacting the same amino acid (c.1070G>C, p.Arg357Pro) has been reported in individuals with hypohidrotic ectodermal dysplasia (Monreal et al. 1998. PubMed ID: 9683615; Goodwin et al. 2014. PubMed ID: 25333067), indicating the p.Arg357 residue may be important for EDA function. Taken together, the c.1069C>T (p.Arg357Trp) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;.
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.69	.;N;.;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N;N;N;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.65
MutPred		0.58		.;Loss of solvent accessibility (P = 0.0087);.;.;
MVP		0.96
MPC		1.8
ClinPred		0.91	D
GERP RS		3.6
Varity_R		0.95
gMVP		0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039347; hg19: chrX-69255352;