NM_001399.5:c.1013C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001399.5(EDA):c.1013C>T(p.Thr338Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,207,869 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. T338A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.29

Publications

15 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 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 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-70035445-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2810309.Status of the report is criteria_provided_single_submitter, 1 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, 0.906

PP5

Variant X-70035446-C-T is Pathogenic according to our data. Variant chrX-70035446-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11048.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.1013C>T	p.Thr338Met	missense_variant	Exon 8 of 8	ENST00000374552.9	NP_001390.1	Q92838-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDA	ENST00000374552.9 link	c.1013C>T	p.Thr338Met	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4	Q92838-1
EDA	ENST00000374553.6 link	c.1007C>T	p.Thr336Met	missense_variant	Exon 8 of 8	1		ENSP00000363681.2	Q92838-3
EDA	ENST00000524573.5 link	c.998C>T	p.Thr333Met	missense_variant	Exon 8 of 8	1		ENSP00000432585.1	Q92838-9
EDA	ENST00000616899.1 link	c.617C>T	p.Thr206Met	missense_variant	Exon 7 of 7	5		ENSP00000481963.1	A0A0C4DGX3

Frequencies

GnomAD3 genomes

AF:

0.00000909

AC:

AN:

109967

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000332

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

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181565

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35179

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

54087

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841957

Other (OTH)

AF:

0.00

AC:

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000909

AC:

AN:

109967

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32205

show subpopulations

African (AFR)

AF:

0.0000332

AC:

AN:

30118

American (AMR)

AF:

0.00

AC:

AN:

10246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2625

East Asian (EAS)

AF:

0.00

AC:

AN:

3509

South Asian (SAS)

AF:

0.00

AC:

AN:

2518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52759

Other (OTH)

AF:

0.00

AC:

AN:

1476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Pathogenic:2

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 338 of the EDA protein (p.Thr338Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with isolated tooth agenesis and hypohidrotic ectodermal dysplasia (PMID: 18545687, 18657636, 27657131). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11048). 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: 19623212). For these reasons, this variant has been classified as Pathogenic. -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked recessive ectodermal dysplasia 1, hypohidrotic (HED; MIM#305100) and X-linked dominant tooth agenesis, selective 1 (TA; MIM#313500). (I) 0108 - This gene is associated with both X-linked recessive and dominant disease. Female carriers of variants causing either condition may be normal or mildly affected, depending on skewed X-inactivation (PMID: 18510547, 16583127). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated TNF domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic in ClinVar, and detected mostly in individuals with non-syndromic tooth agenesis (PMID: 28052341, 34545288, 36071541, 33943035). However, individuals with HED have also been reported (PMID: 27657131, 30417976). Female carriers may be unaffected or present milder features (PMID: 28052341). Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Pathogenic:1

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tooth agenesis, selective, X-linked, 1

Pathogenic:1

Nov 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

.;D;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.9

.;L;.;.

PhyloP100

7.3

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

N;N;N;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Uncertain

0.030

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.66

MutPred

0.82

.;Gain of sheet (P = 0.0477);.;.;

MVP

1.0

MPC

1.9

ClinPred

0.97

GERP RS

5.4

Varity_R

0.95

gMVP

0.87

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

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

Publications

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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