rs132630314

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001399.5(EDA):c.467G>A(p.Arg156His) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.55

Variant links:

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]

EDA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant X-69957097-G-A is Pathogenic according to our data. Variant chrX-69957097-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-69957097-G-A is described in Lovd as [Pathogenic]. Variant chrX-69957097-G-A is described in Lovd as [Pathogenic]. Variant chrX-69957097-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5 linkuse as main transcript	c.467G>A	p.Arg156His	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 linkuse as main transcript	c.467G>A	p.Arg156His	missense_variant	2/8	1	NM_001399.5	ENSP00000363680	P4	Q92838-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112401

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34579

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1097036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362430

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112401

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34579

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 156 of the EDA protein (p.Arg156His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypohidrotic ectodermal dysplasia (PMID: 9683615, 11279189, 11295832, 11416205, 18231121). In at least one individual the variant was observed to be de novo. This variant is also known as c.708G>A (p.R156H). ClinVar contains an entry for this variant (Variation ID: 11037). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects EDA function (PMID: 11416205). This variant disrupts the p.Arg156 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9683615, 11279189, 11416205). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2011	The Arg156His variant in EDA has been reported in at least 18 individuals with X -linked hypohidrotic ectodermal dysplasia (Schneider 2001, Monreal 1998, Schneid er 2011, Vincent 2001, Zhao 2008). This variant was reported as de novo in at le ast 4 individuals with de novo disease and was reported in an individual with a family history of X-linked hypohidrotic ectodermal dysplasia (Schneider 2001, Vi ncent 2001). Furthermore, functional studies have shown that the change to Histi dine (His) at position 156 affects protein cleavage (Chen 2001, Elomaa 2001). In summary, this variant meets our criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Published functional studies demonstrate a damaging effect due to a drastic reduction in the cleavage of ectodysplasin-A as compared to wild-type, preventing the generation of a soluble ectodysplasin-A ligand (Chen et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26273176, 23744313, 26411740, 11416205, 27305980, 26345974, 18231121, 11295832, 11309369, 18076698, 9683615, 11279189, 11378824, 28981473, 21357618, 34426522, 32690319, 32176048, 31924237, 29220840, 31796081, 34863015, 25333067, 17686277, 26502894, 18666859) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T;.;.;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

0.90

L;L;L;.;.

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

N;N;N;N;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.011

D;.;.;D;.

Sift4G

Benign

0.12

T;T;T;T;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.52

MutPred

0.87

Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);Loss of MoRF binding (P = 0.0444);.;.;

MVP

1.0

MPC

0.97

ClinPred

0.82

GERP RS

5.0

Varity_R

0.67

gMVP

0.82

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over