rs397516653

Positions:

• chrX-70035520-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001399.5(EDA):​c.1087A>G​(p.Lys363Glu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.1087A>G	p.Lys363Glu	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.1087A>G	p.Lys363Glu	missense_variant	8/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.1081A>G	p.Lys361Glu	missense_variant	8/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.1072A>G	p.Lys358Glu	missense_variant	8/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.691A>G	p.Lys231Glu	missense_variant	7/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2011

Variant classified as Uncertain Significance - Favor Pathogenic. The Lys363Glu v ariant in EDA has not been reported in the literature nor previously identified by our laboratory. However, this residue is conserved across mammals and computa tional analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Lys363Glu variant may impact the protein. However, this information is not predictive enough to as sume pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	-0.34	.;N;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Uncertain	0.038	D;D;D;T
Polyphen		0.99	D;D;D;.
Vest4		0.74
MutPred		0.65		.;Loss of MoRF binding (P = 0.0024);.;.;
MVP		0.99
MPC		2.0
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516653; hg19: chrX-69255370;