rs142948132

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001399.5(EDA):c.1001G>A(p.Arg334His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,207,703 control chromosomes in the GnomAD database, including 4 homozygotes. There are 137 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00065 ( 1 hom., 22 hem., cov: 21)

Exomes 𝑓: 0.00035 ( 3 hom. 115 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: 9.25

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: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001399.5

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.010842383).

BP6

Variant X-70035434-G-A is Benign according to our data. Variant chrX-70035434-G-A is described in ClinVar as Benign. ClinVar VariationId is 253055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000654 (72/110131) while in subpopulation EAS AF = 0.0146 (51/3501). AF 95% confidence interval is 0.0114. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 72 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5 link	c.1001G>A	p.Arg334His	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.1001G>A	p.Arg334His	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4	Q92838-1
EDA	ENST00000374553.6 link	c.995G>A	p.Arg332His	missense_variant	Exon 8 of 8	1		ENSP00000363681.2	Q92838-3
EDA	ENST00000524573.5 link	c.986G>A	p.Arg329His	missense_variant	Exon 8 of 8	1		ENSP00000432585.1	Q92838-9
EDA	ENST00000616899.1 link	c.605G>A	p.Arg202His	missense_variant	Exon 7 of 7	5		ENSP00000481963.1	A0A0C4DGX3

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

AN:

110077

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000970

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.000396

Gnomad FIN

AF:

0.000345

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000152

Gnomad OTH

AF:

0.000678

GnomAD2 exomes

AF:

0.000920

AC:

166

AN:

180407

AF XY:

0.000705

show subpopulations

Gnomad AFR exome

AF:

0.000539

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00999

Gnomad FIN exome

AF:

0.000253

Gnomad NFE exome

AF:

0.0000500

Gnomad OTH exome

AF:

0.00157

GnomAD4 exome

AF:

0.000354

AC:

389

AN:

1097572

Hom.:

Cov.:

AF XY:

0.000317

AC XY:

115

AN XY:

362942

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26384

American (AMR)

AF:

0.0000284

AC:

AN:

35159

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00504

AC:

152

AN:

30177

South Asian (SAS)

AF:

0.000444

AC:

AN:

54020

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

40481

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000170

AC:

143

AN:

841764

Other (OTH)

AF:

0.00119

AC:

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

100

<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:

0.000654

AC:

AN:

110131

Hom.:

Cov.:

AF XY:

0.000679

AC XY:

AN XY:

32395

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

30220

American (AMR)

AF:

0.0000969

AC:

AN:

10322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2629

East Asian (EAS)

AF:

0.0146

AC:

AN:

3501

South Asian (SAS)

AF:

0.000397

AC:

AN:

2520

European-Finnish (FIN)

AF:

0.000345

AC:

AN:

5805

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000152

AC:

AN:

52741

Other (OTH)

AF:

0.000669

AC:

AN:

1495

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000292

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000692

AC:

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EDA: BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Tooth agenesis, selective, X-linked, 1

Pathogenic:1Benign:1

Aug 17, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

NM_001399.4:c.1001G>A in EDA gene has an allele frequency of 0.011 in East Asian subpopulation in the gnomAD database, including 2 homozygous occurrences, and 54 hemizygotes. This variant was reported in a male patient with Non-syndromic Oligodontia, inherited from his mother, which indicated a X-linked recessive inheritance (PMID: 19278982). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2. -

Hypohidrotic X-linked ectodermal dysplasia

Benign:2

Jul 23, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Nov 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Benign:1

Feb 17, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

1.2

.;L;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

N;N;N;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.025

D;.;.;.

Sift4G

Uncertain

0.044

D;T;D;T

Polyphen

1.0

D;D;D;.

Vest4

0.26

MVP

1.0

MPC

1.5

ClinPred

0.058

GERP RS

5.5

Varity_R

0.89

gMVP

0.86

Mutation Taster

=71/29

polymorphism (auto)

(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