rs132630314

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_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. R156C) 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

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

tooth agenesis, selective, X-linked, 1
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
X-linked hypohidrotic ectodermal dysplasia
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 1 uncertain 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 chrX-69957096-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.

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 VariationId is 11037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5 link	c.467G>A	p.Arg156His	missense_variant	Exon 2 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9 link	c.467G>A	p.Arg156His	missense_variant	Exon 2 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112401

Hom.:

Cov.:

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

African (AFR)

AF:

0.00

AC:

AN:

26379

American (AMR)

AF:

0.00

AC:

AN:

35178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.00

AC:

AN:

30149

South Asian (SAS)

AF:

0.00

AC:

AN:

54023

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841267

Other (OTH)

AF:

0.00

AC:

AN:

46037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112401

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34579

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30952

American (AMR)

AF:

0.00

AC:

AN:

10665

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6131

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53286

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000198

Hom.:

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

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EDA protein function with a negative predictive value of 80%. 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. -

Sep 04, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Pathogenic:1

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jul 27, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

5.6

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

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.67

gMVP

0.82

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over