rs604070

Positions:

chr1-236482370-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_145861.4(EDARADD):c.369C>T(p.Asp123Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,613,874 control chromosomes in the GnomAD database, including 44,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3125 hom., cov: 31)

Exomes 𝑓: 0.23 ( 41725 hom. )

Consequence

EDARADD
NM_145861.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.198

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 1-236482370-C-T is Benign according to our data. Variant chr1-236482370-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236482370-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.198 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4 linkuse as main transcript	c.369C>T	p.Asp123Asp	synonymous_variant	6/6	ENST00000334232.9	NP_665860.2	Q8WWZ3-1
EDARADD	NM_080738.5 linkuse as main transcript	c.339C>T	p.Asp113Asp	synonymous_variant	6/6		NP_542776.1	Q8WWZ3-2
EDARADD	NM_001422628.1 linkuse as main transcript	c.303C>T	p.Asp101Asp	synonymous_variant	8/8		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EDARADD	ENST00000334232.9 linkuse as main transcript	c.369C>T	p.Asp123Asp	synonymous_variant	6/6	1	NM_145861.4	ENSP00000335076.4	Q8WWZ3-1
EDARADD	ENST00000359362.6 linkuse as main transcript	c.339C>T	p.Asp113Asp	synonymous_variant	6/6	1		ENSP00000352320.4	Q8WWZ3-2
EDARADD	ENST00000637660.1 linkuse as main transcript	c.303C>T	p.Asp101Asp	synonymous_variant	6/6	5		ENSP00000490347.1	A0A1B0GV26
EDARADD	ENST00000642595.1 linkuse as main transcript	n.236-9367C>T		intron_variant				ENSP00000494458.1	A0A2R8Y5E0

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28067

AN:

151922

Hom.:

3128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0756

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.282

Gnomad EAS

AF:

0.0920

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.196

GnomAD3 exomes

AF:

0.200

AC:

50249

AN:

251446

Hom.:

5835

AF XY:

0.205

AC XY:

27892

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0709

Gnomad AMR exome

AF:

0.110

Gnomad ASJ exome

AF:

0.268

Gnomad EAS exome

AF:

0.0905

Gnomad SAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.274

Gnomad NFE exome

AF:

0.256

Gnomad OTH exome

AF:

0.218

GnomAD4 exome

AF:

0.233

AC:

340197

AN:

1461834

Hom.:

41725

Cov.:

AF XY:

0.232

AC XY:

168488

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0686

Gnomad4 AMR exome

AF:

0.115

Gnomad4 ASJ exome

AF:

0.267

Gnomad4 EAS exome

AF:

0.0891

Gnomad4 SAS exome

AF:

0.152

Gnomad4 FIN exome

AF:

0.269

Gnomad4 NFE exome

AF:

0.252

Gnomad4 OTH exome

AF:

0.224

GnomAD4 genome

AF:

0.185

AC:

28059

AN:

152040

Hom.:

3125

Cov.:

AF XY:

0.183

AC XY:

13563

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0753

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.282

Gnomad4 EAS

AF:

0.0919

Gnomad4 SAS

AF:

0.141

Gnomad4 FIN

AF:

0.260

Gnomad4 NFE

AF:

0.250

Gnomad4 OTH

AF:

0.197

Alfa

AF:

0.240

Hom.:

8800

Bravo

AF:

0.172

Asia WGS

AF:

0.121

AC:

420

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.253

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Hypohidrotic Ectodermal Dysplasia, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.0

DANN

Benign

0.77

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

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