1-236394504-G-A

Position:

chr1-236394504-G-A

Variant summary

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

The NM_145861.4(EDARADD):c.60G>A(p.Glu20=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,612,996 control chromosomes in the GnomAD database, including 2,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 259 hom., cov: 33)

Exomes 𝑓: 0.021 ( 2563 hom. )

Consequence

EDARADD
NM_145861.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00004923

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.564

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=-0.88).

BP6

Variant 1-236394504-G-A is Benign according to our data. Variant chr1-236394504-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.564 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 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.60G>A	p.Glu20=	splice_region_variant, synonymous_variant	1/6	ENST00000334232.9	NP_665860.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EDARADD	ENST00000334232.9 linkuse as main transcript	c.60G>A	p.Glu20=	splice_region_variant, synonymous_variant	1/6	1	NM_145861.4	ENSP00000335076	Q8WWZ3-1
EDARADD	ENST00000439430.5 linkuse as main transcript	c.-5-14712G>A		intron_variant		3		ENSP00000405815
EDARADD	ENST00000637660.1 linkuse as main transcript	c.-5-14712G>A		intron_variant		5		ENSP00000490347

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3441

AN:

152152

Hom.:

258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.0767

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00648

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0467

AC:

11696

AN:

250330

Hom.:

1135

AF XY:

0.0447

AC XY:

6039

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0811

Gnomad ASJ exome

AF:

0.00519

Gnomad EAS exome

AF:

0.313

Gnomad SAS exome

AF:

0.0634

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.0291

GnomAD4 exome

AF:

0.0208

AC:

30339

AN:

1460726

Hom.:

2563

Cov.:

AF XY:

0.0216

AC XY:

15664

AN XY:

726596

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.0773

Gnomad4 ASJ exome

AF:

0.00479

Gnomad4 EAS exome

AF:

0.320

Gnomad4 SAS exome

AF:

0.0630

Gnomad4 FIN exome

AF:

0.0118

Gnomad4 NFE exome

AF:

0.00559

Gnomad4 OTH exome

AF:

0.0285

GnomAD4 genome

AF:

0.0226

AC:

3436

AN:

152270

Hom.:

259

Cov.:

AF XY:

0.0255

AC XY:

1896

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.0455

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.0763

Gnomad4 FIN

AF:

0.0144

Gnomad4 NFE

AF:

0.00648

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0191

Hom.:

507

Bravo

AF:

0.0275

Asia WGS

AF:

0.159

AC:

552

AN:

3478

EpiCase

AF:

0.00627

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -

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 29, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.0

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.014

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