X-70035393-T-G

Position:

• chrX-70035393-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001399.5(EDA):​c.960T>G​(p.Tyr320*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.527

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 8 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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70035393-T-G is Pathogenic according to our data. Variant chrX-70035393-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 228339.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.960T>G	p.Tyr320*	stop_gained	8/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.960T>G	p.Tyr320*	stop_gained	8/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.954T>G	p.Tyr318*	stop_gained	8/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.945T>G	p.Tyr315*	stop_gained	8/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.564T>G	p.Tyr188*	stop_gained	7/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

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

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 10, 2015

The p.Tyr320X variant in EDA has not been previously reported in individuals wit h hypohidrotic ectodermal dysplasia (HED) and was absent from large population s tudies. This nonsense variant leads to a premature termination codon at position 320, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the EDA gene is an established disease mechanism in X-linked HED. In summary, this variant meets our criteria to be classified as pathogeni c for HED in an X-linked manner (http://www.partners.org/personalizedmedicine/LM M) based upon absence from controls and predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	35
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.65	D
Vest4		0.79
GERP RS		-2.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657687; hg19: chrX-69255243;