X-70035394-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001399.5(EDA):c.961G>T(p.Glu321Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70035394-G-T is Pathogenic according to our data. Variant chrX-70035394-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-70035394-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.961G>T	p.Glu321Ter	stop_gained	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.961G>T	p.Glu321Ter	stop_gained	8/8	1	NM_001399.5	P4
EDA	ENST00000374553.6	c.955G>T	p.Glu319Ter	stop_gained	8/8	1		A1
EDA	ENST00000524573.5	c.946G>T	p.Glu316Ter	stop_gained	8/8	1		A1
EDA	ENST00000616899.1	c.565G>T	p.Glu189Ter	stop_gained	7/7	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 17, 2011

The Glu321X variant in EDA has been reported in one individual with X-linked hyp ohidrotic ectodermal dysplasia and was absent from 60 control X chromosomes (Mon real 1998). In addition, this variant leads to a premature stop codon at positi on 321, which is predicted to result in a truncated or absent protein. Heterozyg ous and hemizygous loss of function of the EDA gene is an established disease me chanism in XLHED. Therefore, this variant is highly likely to be pathogenic. -

EDA-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

The EDA c.961G>T variant is predicted to result in premature protein termination (p.Glu321*). This variant was reported in an individual with X-linked hypohidrotic ectodermal dysplasia (reported as G1202T/E321Ter in Monreal et al. 1998. PubMed ID: 9683615). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in EDA are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	41
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.80
GERP RS		5.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516682; hg19: chrX-69255244;