rs727503011

chrX-70035424-C-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.991C>T(p.Gln331Ter) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q331Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.29

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 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 45 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70035424-C-T is Pathogenic according to our data. Variant chrX-70035424-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 163324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70035424-C-T is described in Lovd as [Pathogenic]. Variant chrX-70035424-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.991C>T	p.Gln331Ter	stop_gained	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.991C>T	p.Gln331Ter	stop_gained	8/8	1	NM_001399.5	P4
EDA	ENST00000374553.6	c.985C>T	p.Gln329Ter	stop_gained	8/8	1		A1
EDA	ENST00000524573.5	c.976C>T	p.Gln326Ter	stop_gained	8/8	1		A1
EDA	ENST00000616899.1	c.595C>T	p.Gln199Ter	stop_gained	7/7	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2014	The Gln331X variant in EDA has been previously reported in one individual with X -linked hypohidrotic ectodermal dysplasia (XLHED; Dietz 2013). The Gln331X nonse nse variant leads to a premature termination codon at position 331, which is pre dicted to lead to a truncated or absent protein. Loss of function of the EDA gen e is an established disease mechanism in XLHED. In summary, this variant meets o ur criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 12, 2022	ClinVar contains an entry for this variant (Variation ID: 163324). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the EDA protein in which other variant(s) (p.Ala367Valfs*10) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with ectodermal dysplasia (PMID: 23553579). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln331*) in the EDA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the EDA protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	39
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.77
GERP RS		5.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503011; hg19: chrX-69255274; COSMIC: COSV65781266; COSMIC: COSV65781266;