rs966365

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_StrongBA1

The NM_145861.4(EDARADD):c.27G>A(p.Met9Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,613,834 control chromosomes in the GnomAD database, including 569,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46083 hom., cov: 32)

Exomes 𝑓: 0.84 ( 523143 hom. )

Consequence

EDARADD
NM_145861.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0690

Publications

39 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 -17 ACMG points.

PM1

In a chain Ectodysplasin-A receptor-associated adapter protein (size 214) in uniprot entity EDAD_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_145861.4

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=8.9501276E-7).

BP6

Variant 1-236394471-G-A is Benign according to our data. Variant chr1-236394471-G-A is described in ClinVar as [Benign]. Clinvar id is 262600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4 link	c.27G>A	p.Met9Ile	missense_variant	Exon 1 of 6	ENST00000334232.9	NP_665860.2	Q8WWZ3-1
EDARADD	NM_001422628.1 link	c.-5-14745G>A		intron_variant	Intron 3 of 7		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDARADD	ENST00000334232.9 link	c.27G>A	p.Met9Ile	missense_variant	Exon 1 of 6	1	NM_145861.4	ENSP00000335076.4	Q8WWZ3-1
EDARADD	ENST00000637660.1 link	c.-5-14745G>A		intron_variant	Intron 1 of 5	5		ENSP00000490347.1	A0A1B0GV26
EDARADD	ENST00000439430.5 link	c.-5-14745G>A		intron_variant	Intron 3 of 7	3		ENSP00000405815.1	B1AL55

Frequencies

GnomAD3 genomes

AF:

0.766

AC:

116539

AN:

152054

Hom.:

46074

Cov.:

show subpopulations

Gnomad AFR

AF:

0.552

Gnomad AMI

AF:

0.841

Gnomad AMR

AF:

0.858

Gnomad ASJ

AF:

0.847

Gnomad EAS

AF:

0.919

Gnomad SAS

AF:

0.917

Gnomad FIN

AF:

0.814

Gnomad MID

AF:

0.867

Gnomad NFE

AF:

0.841

Gnomad OTH

AF:

0.780

GnomAD2 exomes

AF:

0.841

AC:

211467

AN:

251440

AF XY:

0.848

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.907

Gnomad ASJ exome

AF:

0.851

Gnomad EAS exome

AF:

0.919

Gnomad FIN exome

AF:

0.817

Gnomad NFE exome

AF:

0.837

Gnomad OTH exome

AF:

0.831

GnomAD4 exome

AF:

0.844

AC:

1233814

AN:

1461662

Hom.:

523143

Cov.:

AF XY:

0.847

AC XY:

615718

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.536

AC:

17936

AN:

33476

American (AMR)

AF:

0.900

AC:

40239

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.846

AC:

22102

AN:

26136

East Asian (EAS)

AF:

0.944

AC:

37486

AN:

39692

South Asian (SAS)

AF:

0.911

AC:

78545

AN:

86246

European-Finnish (FIN)

AF:

0.815

AC:

43520

AN:

53410

Middle Eastern (MID)

AF:

0.846

AC:

4878

AN:

5768

European-Non Finnish (NFE)

AF:

0.844

AC:

938900

AN:

1111826

Other (OTH)

AF:

0.831

AC:

50208

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

9457

18914

28372

37829

47286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.766

AC:

116587

AN:

152172

Hom.:

46083

Cov.:

AF XY:

0.772

AC XY:

57396

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.551

AC:

22871

AN:

41478

American (AMR)

AF:

0.858

AC:

13125

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.847

AC:

2940

AN:

3472

East Asian (EAS)

AF:

0.919

AC:

4763

AN:

5184

South Asian (SAS)

AF:

0.916

AC:

4412

AN:

4814

European-Finnish (FIN)

AF:

0.814

AC:

8622

AN:

10586

Middle Eastern (MID)

AF:

0.871

AC:

256

AN:

294

European-Non Finnish (NFE)

AF:

0.841

AC:

57195

AN:

68028

Other (OTH)

AF:

0.776

AC:

1638

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1255

2509

3764

5018

6273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.815

Hom.:

155604

Bravo

AF:

0.759

TwinsUK

AF:

0.846

AC:

3138

ALSPAC

AF:

0.845

AC:

3256

ESP6500AA

AF:

0.540

AC:

2381

ESP6500EA

AF:

0.840

AC:

7222

ExAC

AF:

0.831

AC:

100867

Asia WGS

AF:

0.866

AC:

3010

AN:

3478

EpiCase

AF:

0.842

EpiControl

AF:

0.848

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: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

- -

Hypohidrotic Ectodermal Dysplasia, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.8

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.051

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.43

MetaRNN

Benign

9.0e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

-0.069

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.36

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.041

MutPred

0.085

Loss of ubiquitination at K14 (P = 0.0613);

MPC

0.66

ClinPred

0.018

GERP RS

1.3

PromoterAI

0.0066

Neutral

(source)

Varity_R

0.70

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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rs966365

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