X-70035478-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001399.5(EDA):​c.1045G>T​(p.Ala349Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,207,559 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 Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant X-70035478-G-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.1045G>T	p.Ala349Ser	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>T	p.Ala349Ser	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.1039G>T	p.Ala347Ser	missense_variant	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.1030G>T	p.Ala344Ser	missense_variant	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.649G>T	p.Ala217Ser	missense_variant	Exon 7 of 7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109377 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31665

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098182 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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109377 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31665

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000190

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

May 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 349 of the EDA protein (p.Ala349Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EDA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1470331). 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. This variant disrupts the p.Ala349 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9683615, 15461765). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.72	N;N;N;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.015	D;D;D;T
Polyphen		0.99	D;D;D;.
Vest4		0.72
MutPred		0.59		.;Gain of glycosylation at A349 (P = 0.0421);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.95

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;