rs114632254

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_145861.4(EDARADD):c.308C>T(p.Ser103Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,052 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 48 hom., cov: 32)

Exomes 𝑓: 0.027 ( 656 hom. )

Consequence

EDARADD
NM_145861.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.62

Publications

13 publications found

Variant links:

Genes affected

EDARADD (HGNC:14341): (EDAR associated via death domain) This gene was identified by its association with ectodermal dysplasia, a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands. The protein encoded by this gene is a death domain-containing protein, and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth and other ectodermal derivatives. This protein and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth. Through its interaction with EDAR, this protein acts as an adaptor, and links the receptor to downstream signaling pathways. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

EDARADD Gene-Disease associations (from GenCC):

ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant
Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant hypohidrotic ectodermal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hypohidrotic ectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EDARADD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.1424 (below the threshold of 3.09). Trascript score misZ: 1.2505 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive hypohidrotic ectodermal dysplasia, autosomal dominant hypohidrotic ectodermal dysplasia, tooth agenesis, ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive, ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant.

BP4

Computational evidence support a benign effect (MetaRNN=0.00474298).

BP6

Variant 1-236482309-C-T is Benign according to our data. Variant chr1-236482309-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0212 (3221/152182) while in subpopulation AMR AF = 0.0308 (471/15270). AF 95% confidence interval is 0.0294. There are 48 homozygotes in GnomAd4. There are 1586 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4 link	c.308C>T	p.Ser103Phe	missense_variant	Exon 6 of 6	ENST00000334232.9	NP_665860.2	Q8WWZ3-1
EDARADD	NM_080738.5 link	c.278C>T	p.Ser93Phe	missense_variant	Exon 6 of 6		NP_542776.1	Q8WWZ3-2
EDARADD	NM_001422628.1 link	c.242C>T	p.Ser81Phe	missense_variant	Exon 8 of 8		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9 link	c.308C>T	p.Ser103Phe	missense_variant	Exon 6 of 6	1	NM_145861.4	ENSP00000335076.4		Q8WWZ3-1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3224

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00512

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0309

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.0296

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0305

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0213

AC:

5347

AN:

251476

AF XY:

0.0221

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.0186

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0269

Gnomad NFE exome

AF:

0.0301

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0272

AC:

39768

AN:

1461870

Hom.:

656

Cov.:

AF XY:

0.0272

AC XY:

19753

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00424

AC:

142

AN:

33480

American (AMR)

AF:

0.0192

AC:

858

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

324

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0117

AC:

1005

AN:

86256

European-Finnish (FIN)

AF:

0.0277

AC:

1479

AN:

53418

Middle Eastern (MID)

AF:

0.0383

AC:

221

AN:

5768

European-Non Finnish (NFE)

AF:

0.0309

AC:

34344

AN:

1111992

Other (OTH)

AF:

0.0231

AC:

1394

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2173

4346

6520

8693

10866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1274

2548

3822

5096

6370

<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:

0.0212

AC:

3221

AN:

152182

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

1586

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00511

AC:

212

AN:

41522

American (AMR)

AF:

0.0308

AC:

471

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00870

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0296

AC:

314

AN:

10598

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0305

AC:

2074

AN:

68012

Other (OTH)

AF:

0.0251

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

159

318

478

637

796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0265

Hom.:

178

Bravo

AF:

0.0203

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0298

AC:

115

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0274

AC:

236

ExAC

AF:

0.0211

AC:

2559

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0317

EpiControl

AF:

0.0366

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 31796081, 23991204, 21626677, 27665865, 29705498) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ectodermal dysplasia

Benign:1

Sep 25, 2024

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1_strong, BS2_strong, BP4_supporting -

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive;C3541517:Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Mar 02, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;.;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

2.0

.;.;M;.

PhyloP100

2.6

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.6

.;D;D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0040

.;D;D;D

Sift4G

Uncertain

0.011

.;D;D;D

Polyphen

0.92

.;.;P;.

Vest4

0.11, 0.16

MPC

1.4

ClinPred

0.030

GERP RS

5.2

Varity_R

0.16

gMVP

0.29

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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