rs1556039088

chrX-69957109-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001399.5(EDA):c.479G>A(p.Ser160Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S160R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.55

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.

• PM1: In a chain Ectodysplasin-A, secreted form (size 231) in uniprot entity EDA_HUMAN there are 151 pathogenic changes around while only 13 benign (92%) in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-69957109-G-A is Pathogenic according to our data. Variant chrX-69957109-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 458657.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.479G>A	p.Ser160Asn	missense_variant	2/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.479G>A	p.Ser160Asn	missense_variant	2/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2021

For these reasons, this variant has been classified as Pathogenic. 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 has been observed in individual(s) with clinical features of hypohidrotic ectodermal dysplasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 458657). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 160 of the EDA protein (p.Ser160Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.20	N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.17	N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.12	T;.;.;T;.
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.98	D;D;D;.;.
Vest4		0.39
MutPred		0.28		Loss of phosphorylation at S160 (P = 0.0073);Loss of phosphorylation at S160 (P = 0.0073);Loss of phosphorylation at S160 (P = 0.0073);.;.;
MVP		0.98
MPC		1.2
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.66
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: rs1556039088; hg19: chrX-69176959;