rs397516654

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

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:6O:1

Conservation

PhyloP100: 4.35

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 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 id is 1482275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5 linkuse as main transcript	c.1094T>C	p.Val365Ala	missense_variant	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9 linkuse as main transcript	c.1094T>C	p.Val365Ala	missense_variant	8/8	1	NM_001399.5	P4	Q92838-1
EDA	ENST00000374553.6 linkuse as main transcript	c.1088T>C	p.Val363Ala	missense_variant	8/8	1		A1	Q92838-3
EDA	ENST00000524573.5 linkuse as main transcript	c.1079T>C	p.Val360Ala	missense_variant	8/8	1		A1	Q92838-9
EDA	ENST00000616899.1 linkuse as main transcript	c.698T>C	p.Val233Ala	missense_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

107573

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

29983

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

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182595

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67417

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000379

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:

0.0000558

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000279

AC:

AN:

107573

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

29983

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:

0.0000575

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Pathogenic:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	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). 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. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2017

- -

EDA-related disorders

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

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. -

Partial congenital absence of teeth

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 20, 2011

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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2022

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) -

Tooth agenesis, selective, X-linked, 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Aug 12, 2023

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

Dann

Uncertain

0.99

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

MutationTaster

Benign

1.0

D;D;D

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

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