rs727503010

Positions:

• chrX-70035380-AC-A

Variant summary

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

The ENST00000374552.9(EDA):​c.948del​(p.Phe317LeufsTer57) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA ENST00000374552.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.46

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 92 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70035380-AC-A is Pathogenic according to our data. Variant chrX-70035380-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 163323.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.948del	p.Phe317LeufsTer57	frameshift_variant	8/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.948del	p.Phe317LeufsTer57	frameshift_variant	8/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.942del	p.Phe315LeufsTer57	frameshift_variant	8/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.933del	p.Phe312LeufsTer57	frameshift_variant	8/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.552del	p.Phe185LeufsTer57	frameshift_variant	7/7	5		ENSP00000481963

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

Nov 03, 2014

The p.Phe317fs variant in EDA has not been previously reported in individuals or any other families with clinical features of X-linked hypohidrotic extodermal d ysplasia (XLHED) and was absent from large population studies. This variant is p redicted to cause a frameshift, which alters the protein?s amino acid sequence b eginning at position 317 and leads to a premature termination codon 57 amino aci ds downstream. This alteration is then predicted to lead to a truncated or absen t protein. Heterozygous loss of function of function of the EDA gene is an estab lished disease mechanism in XLHED. In summary, this variant meets our criteria t o be classified as pathogenic for XLHED in an X-linked manner (http://www.partne rs.org/personalizedmedicine/LMM). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503010; hg19: chrX-69255230;