rs397516676

Positions:

• chrX-70033424-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001399.5(EDA):​c.822del​(p.Trp274CysfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.36

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 18 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-70033424-TG-T is Pathogenic according to our data. Variant chrX-70033424-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 44210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.822del	p.Trp274CysfsTer6	frameshift_variant	7/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.822del	p.Trp274CysfsTer6	frameshift_variant	7/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2021	This sequence change creates a premature translational stop signal (p.Trp274Cysfs*6) in the EDA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with ectodermal dysplasia (PMID: 23687000, 25333067). ClinVar contains an entry for this variant (Variation ID: 44210). This variant is not present in population databases (ExAC no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 22, 2011	The Trp274CysfsX6 variant in EDA has not been reported in the literature nor pre viously identified by our laboratory. However, the Trp274CysfsX6 variant is pred icted to cause a frameshift, which alters the protein's amino acid sequence begi nning at codon 274 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to lead to a truncated or absent protein. In summa ry, this variant meets our criteria to be classified as pathogenic. -

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: rs397516676; hg19: chrX-69253274;