rs132630317

Variant names:

• chrX-70035478-G-A
• rs132630317
• NM_001399.5:c.1045G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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 (★★).

• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.1045G>A	p.Ala349Thr	missense_variant	Exon 8 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.1045G>A	p.Ala349Thr	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.1039G>A	p.Ala347Thr	missense_variant	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.1030G>A	p.Ala344Thr	missense_variant	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.649G>A	p.Ala217Thr	missense_variant	Exon 7 of 7	5		ENSP00000481963.1

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

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EDA protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.
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;