rs1556110180

Positions:

• chrX-70035374-T-C

Variant summary

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

The NM_001399.5(EDA):​c.941T>C​(p.Phe314Ser) 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.19

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, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.941T>C	p.Phe314Ser	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.941T>C	p.Phe314Ser	missense_variant	8/8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.935T>C	p.Phe312Ser	missense_variant	8/8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.926T>C	p.Phe309Ser	missense_variant	8/8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.545T>C	p.Phe182Ser	missense_variant	7/7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been observed in individuals affected with clinical features of ectodermal dysplasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 528356). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 314 of the EDA protein (p.Phe314Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.73	.;N;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.66	N;N;N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Benign	0.72	T;T;T;T
Polyphen		1.0	D;P;D;.
Vest4		0.81
MutPred		0.71		.;Loss of stability (P = 0.0757);.;.;
MVP		1.0
MPC		1.8
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.90
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: rs1556110180; hg19: chrX-69255224;