X-70035394-G-T

Variant names:

• chrX-70035394-G-T
• rs397516682
• NM_001399.5:c.961G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001399.5(EDA):​c.961G>T​(p.Glu321*) 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:3
• Conservation: PhyloP100: 9.22
• Publications: 3 publications found

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]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 43 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 VariationId is 44216.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.961G>T	p.Glu321*	stop_gained	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.961G>T	p.Glu321*	stop_gained	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.955G>T	p.Glu319*	stop_gained	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.946G>T	p.Glu316*	stop_gained	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.565G>T	p.Glu189*	stop_gained	Exon 7 of 7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Sep 17, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

not provided Pathogenic:1

Nov 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 71 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26345974, 12949972, 9683615) -

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
PhyloP100		9.2
Vest4		0.80
GERP RS		5.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516682; hg19: chrX-69255244;