rs397516654

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 13P and 4B. PM1PM5PP2PP5_Very_StrongBS2

The NM_001399.5(EDA):c.1094T>C(p.Val365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000431 in 1,205,588 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V365M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000045 ( 0 hom. 13 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 4.35

Publications

2 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_001399.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-70035526-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1482275.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.

PP5

Variant X-70035527-T-C is Pathogenic according to our data. Variant chrX-70035527-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 49 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5 link	c.1094T>C	p.Val365Ala	missense_variant	Exon 8 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EDA	ENST00000374552.9 link	c.1094T>C	p.Val365Ala	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6 link	c.1088T>C	p.Val363Ala	missense_variant	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5 link	c.1079T>C	p.Val360Ala	missense_variant	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1 link	c.698T>C	p.Val233Ala	missense_variant	Exon 7 of 7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

107573

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:

0.0000575

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182595

AF XY:

0.0000148

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1098015

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363371

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

841954

Other (OTH)

AF:

0.0000217

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000279

AC:

AN:

107573

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

29983

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29419

American (AMR)

AF:

0.00

AC:

AN:

9807

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2581

East Asian (EAS)

AF:

0.00

AC:

AN:

3420

South Asian (SAS)

AF:

0.00

AC:

AN:

2349

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000575

AC:

AN:

52170

Other (OTH)

AF:

0.00

AC:

AN:

1422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Pathogenic:1Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Pathogenic and reported on 10-31-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 365 of the EDA protein (p.Val365Ala). This variant is present in population databases (rs397516654, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with selective tooth agenesis in a single, large family (PMID: 19623212). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44185). 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: 19623212). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 22, 2017

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EDA-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been observed to segregate with disease in a family with multiple individuals with selective tooth agenesis (PMID: 19623212). Functional studies suggest that the c.1094T>C (p.Val365Ala) variant may affect cell signaling pathways (PMID: 19623212). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001095% (2/182595) and thus is presumed to be rare. The c.1094T>C (p.Val365Ala) variant affects a highly conserved amino acid. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.1094T>C p.Val365Ala variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Jun 24, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with reduced receptor binding and signaling capability compared to wildtype (Mues et al., 2010); 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: 19623212, 24391090, 20628232, 25203534, 21457804, 26325558, 19921643, 11295832, 23553579, 26345974, 24664614, 12949972, 22350046) -

Hypodontia

Pathogenic:1

Sep 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Val365Ala variant in EDA has been reported in one family with X-linked non-s yndromic tooth agenesis, showing segregation with clinical features in at least 6 meioses in this family. In addition, this variant was absent from over 140 co ntrol chromosomes (Mues 2010). Valine (Val) at position 365 is highly conserved across evolutionarily distant species suggesting that a change to the amino acid may not be tolerated. However, computational analyses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. Furthermore, functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010). In summ ary, this variant is likely to be pathogenic in association with tooth agenesis, but its role the hypohidrotic ectodermal dysplasia phenotype remains unclear. -

Tooth agenesis, selective, X-linked, 1

Pathogenic:1

Aug 12, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This EDA variant (rs397516654) is rare (<0.1%) in a large population dataset (gnomAD: 2/182595 total alleles; 0.001%; 1 hemizygote) and has been reported in ClinVar. This variant has been reported in a multi-generation family with X-linked nonsyndromic tooth agenesis. This amino acid substitution is located in the C-terminal quarter of the TNF-like receptor-binding domain, near the dimer interface where receptor binding is predicted to occur; in vitro experimental studies demonstrate that the signaling capacity of protein constructs containing p.Val365Ala are impaired even though cellular production, export and receptor binding are readily detectable. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1094T>C (p.Val365Ala) to be likely pathogenic for X-linked selected tooth agenesis-1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

.;D;.;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

T;T;T;T

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.35

.;N;.;.

PhyloP100

4.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.52

N;N;N;.

REVEL

Pathogenic

0.67

Sift

Benign

0.047

D;.;.;.

Sift4G

Benign

0.087

T;T;T;T

Polyphen

0.39

B;B;B;.

Vest4

0.16

MVP

1.0

MPC

1.1

ClinPred

0.46

GERP RS

5.4

Varity_R

0.83

gMVP

0.89

Mutation Taster

=32/68

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over