rs966365

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 15/20 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

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 -18 ACMG points.

PM1

In a chain Ectodysplasin-A receptor-associated adapter protein (size 214) in uniprot entity EDAD_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_145861.4

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. Variant chr1-236394471-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
EDARADD	NM_145861.4 linkuse as main transcript	c.27G>A	p.Met9Ile	missense_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.27G>A	p.Met9Ile	missense_variant	1/6	1	NM_145861.4	ENSP00000335076	Q8WWZ3-1
EDARADD	ENST00000439430.5 linkuse as main transcript	c.-5-14745G>A		intron_variant		3		ENSP00000405815
EDARADD	ENST00000637660.1 linkuse as main transcript	c.-5-14745G>A		intron_variant		5		ENSP00000490347

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

GnomAD3 exomes

AF:

0.841

AC:

211467

AN:

251440

Hom.:

90008

AF XY:

0.848

AC XY:

115210

AN XY:

135886

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 SAS exome

AF:

0.912

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

Gnomad4 AFR exome

AF:

0.536

Gnomad4 AMR exome

AF:

0.900

Gnomad4 ASJ exome

AF:

0.846

Gnomad4 EAS exome

AF:

0.944

Gnomad4 SAS exome

AF:

0.911

Gnomad4 FIN exome

AF:

0.815

Gnomad4 NFE exome

AF:

0.844

Gnomad4 OTH exome

AF:

0.831

GnomAD4 genome

AF:

0.766

AC:

116587

AN:

152172

Hom.:

46083

Cov.:

AF XY:

0.772

AC XY:

57396

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.551

Gnomad4 AMR

AF:

0.858

Gnomad4 ASJ

AF:

0.847

Gnomad4 EAS

AF:

0.919

Gnomad4 SAS

AF:

0.916

Gnomad4 FIN

AF:

0.814

Gnomad4 NFE

AF:

0.841

Gnomad4 OTH

AF:

0.776

Alfa

AF:

0.829

Hom.:

111674

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Hypohidrotic Ectodermal Dysplasia, Recessive

Benign:1

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

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

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

MutationTaster

Benign

1.0

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

Varity_R

0.70

gMVP

0.11

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

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