rs132630311

Positions:

• chrX-69616495-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001399.5(EDA):​c.187G>A​(p.Glu63Lys) variant causes a missense change. 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 (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.88

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant X-69616495-G-A is Pathogenic according to our data. Variant chrX-69616495-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11034.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-69616495-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.187G>A	p.Glu63Lys	missense_variant	1/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.187G>A	p.Glu63Lys	missense_variant	1/8	1	NM_001399.5	ENSP00000363680	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;.;.;T;.
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N;N;N;N;N;N
MutationTaster	Benign	0.97	A;A;A;A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D;D;D;N;N;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;T;T;T
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.83
MutPred		0.79		Gain of ubiquitination at E63 (P = 0.0211);Gain of ubiquitination at E63 (P = 0.0211);Gain of ubiquitination at E63 (P = 0.0211);Gain of ubiquitination at E63 (P = 0.0211);Gain of ubiquitination at E63 (P = 0.0211);Gain of ubiquitination at E63 (P = 0.0211);
MVP		1.0
MPC		0.88
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs132630311; hg19: chrX-68836339;