rs727505089

Positions:

• chrX-69616438-C-CTGGG

Variant summary

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

The NM_001399.5(EDA):​c.132_135dup​(p.Phe46GlyfsTer55) 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 (★). Synonymous variant affecting the same amino acid position (i.e. L44L) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.02

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-69616438-C-CTGGG is Pathogenic according to our data. Variant chrX-69616438-C-CTGGG is described in ClinVar as [Pathogenic]. Clinvar id is 179733.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.132_135dup	p.Phe46GlyfsTer55	frameshift_variant	1/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.132_135dup	p.Phe46GlyfsTer55	frameshift_variant	1/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

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

Apr 08, 2014

The Phe46fs variant in EDA has not been previously reported in individuals with hypohidrotic ectodermal dysplasia and was absent from large population studies. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 46 and lead to a premature termination codon 55 amino aci ds downstream. This alteration is then predicted to lead to a truncated or absen t protein. Loss of function of function of the EDA gene is an established diseas e mechanism in XLHED. In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/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: rs727505089; hg19: chrX-68836282;