rs387907197

Positions:

• chrX-70033430-C-G
• chrX-70033430-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001399.5(EDA):​c.826C>G​(p.Arg276Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 112,350 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.85

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant X-70033430-C-G is Pathogenic according to our data. Variant chrX-70033430-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2417023.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.826C>G	p.Arg276Gly	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.826C>G	p.Arg276Gly	missense_variant	7/8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112350 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34508

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112350 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34508

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 06, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 276 of the EDA protein (p.Arg276Gly). This variant has not been reported in the literature in individuals affected with EDA-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg276 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19921643, 21357618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	N;N;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;N;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0070	D;.;.;.
Sift4G	Uncertain	0.042	D;D;T;T
Polyphen		0.99	D;D;D;.
Vest4		0.74
MutPred		0.60		Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);.;.;
MVP		0.99
MPC		2.0
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907197; hg19: chrX-69253280;