rs132630317

Positions:

• chrX-70035478-G-A
• chrX-70035478-G-T

Variant summary

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

The NM_001399.5(EDA):​c.1045G>A​(p.Ala349Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. A349S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.25

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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-70035478-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1470331.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant X-70035478-G-A is Pathogenic according to our data. Variant chrX-70035478-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70035478-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.1045G>A	p.Ala349Thr	missense_variant	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.1045G>A	p.Ala349Thr	missense_variant	8/8	1	NM_001399.5	P4
EDA	ENST00000374553.6	c.1039G>A	p.Ala347Thr	missense_variant	8/8	1		A1
EDA	ENST00000524573.5	c.1030G>A	p.Ala344Thr	missense_variant	8/8	1		A1
EDA	ENST00000616899.1	c.649G>A	p.Ala217Thr	missense_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098180 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

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, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 349 of the EDA protein (p.Ala349Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 9683615, 15461765). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11040). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2023

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: 11343303, 18666859, 21457804, 30192988, 15461765, 35131284, 22446708, 22566850, 30117778, 31129666, 24312213, 11295832, 9683615, 34863015, 26582918, 24077912) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	.;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.89
MutPred		0.89		.;Loss of sheet (P = 0.0817);.;.;
MVP		1.0
MPC		1.8
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs132630317; hg19: chrX-69255328; COSMIC: COSV105927890; COSMIC: COSV105927890;