rs727504649

Positions:

• chrX-69957104-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001399.5(EDA):​c.474A>C​(p.Lys158Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.41

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 region_of_interest Disordered (size 99) in uniprot entity EDA_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-69957104-A-C is Pathogenic according to our data. Variant chrX-69957104-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 179127.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.474A>C	p.Lys158Asn	missense_variant	2/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.474A>C	p.Lys158Asn	missense_variant	2/8	1	NM_001399.5	ENSP00000363680	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 11, 2013

The Lys158Asn variant in EDA has been reported in one individual with X-linked h ypohidrotic ectodermal dysplasia (XLHED). It should be noted that this individua l has a different nucleotide change (c.474A>T) which results in the same Lys158A sn amino acid change (Schneider 2001). In vitro studies have shown that the Lys1 58Asn variant alters the normal function of the protein by impacting a critica l furin cleavage site. Several other pathogenic changes in this region are repo rted in individuals with XLHED and are shown to impact protein function as well (Chen 2001). These functional studies indicate that variants in the furin cleava ge site region are disease causing. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;.;.
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.69	N;N;N;.;.
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.85	N;N;N;N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D;.;.;D;.
Sift4G	Uncertain	0.025	D;D;D;D;D
Polyphen		0.99	D;D;D;.;.
Vest4		0.46
MutPred		0.74		Loss of methylation at K158 (P = 0.0037);Loss of methylation at K158 (P = 0.0037);Loss of methylation at K158 (P = 0.0037);.;.;
MVP		0.96
MPC		0.91
ClinPred		0.69	D
GERP RS		2.5
Varity_R		0.51
gMVP		0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504649; hg19: chrX-69176954;