rs397516681

Positions:

• chrX-70033506-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001399.5(EDA):​c.902A>G​(p.Tyr301Cys) variant causes a missense 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.72

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 8) in uniprot entity EDA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-70033506-A-G is Pathogenic according to our data. Variant chrX-70033506-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44215.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.902A>G	p.Tyr301Cys	missense_variant	7/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.902A>G	p.Tyr301Cys	missense_variant	7/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.902A>G	p.Tyr301Cys	missense_variant	7/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.893A>G	p.Tyr298Cys	missense_variant	7/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.506A>G	p.Tyr169Cys	missense_variant	6/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2012

The Tyr301Cys variant in EDA has been reported in one individual with X-linked h ypohidrotic ectodermal dysplasia (Zhang 2011). This variant falls within the TNF domain of the protein and variants in this region are believed to greatly impac t protein function (Zhang 2011). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Tyr301Cys variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, this variant is likely to be pathogenic, though additional data is required to fully establish the pathogenic ity of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.99
MutPred		0.86		Loss of catalytic residue at L296 (P = 0.094);Loss of catalytic residue at L296 (P = 0.094);.;.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516681; hg19: chrX-69253356;