rs397516682

Positions:

• chrX-70035394-G-A
• chrX-70035394-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000374552.9(EDA):​c.961G>A​(p.Glu321Lys) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA ENST00000374552.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

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 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000374552.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.961G>A	p.Glu321Lys	missense_variant	8/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.961G>A	p.Glu321Lys	missense_variant	8/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.955G>A	p.Glu319Lys	missense_variant	8/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.946G>A	p.Glu316Lys	missense_variant	8/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.565G>A	p.Glu189Lys	missense_variant	7/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	.;D;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	.;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.77	N;N;N;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Benign	0.12	T;D;T;D
Polyphen		1.0	D;D;D;.
Vest4		0.66
MutPred		0.68		.;Gain of methylation at E321 (P = 0.0099);.;.;
MVP		1.0
MPC		2.0
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516682; hg19: chrX-69255244;