2-108897145-A-G

Position:

chr2-108897145-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_022336.4(EDAR):c.1109T>C(p.Val370Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,613,832 control chromosomes in the GnomAD database, including 23,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V370L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.070 ( 2877 hom., cov: 32)

Exomes 𝑓: 0.047 ( 20942 hom. )

Consequence

EDAR
NM_022336.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:9O:1

Conservation

PhyloP100: 8.95

Variant links:

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

EDAR links:

RANBP2 (HGNC:):

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_022336.4

BP4

Computational evidence support a benign effect (MetaRNN=9.223032E-7).

BP6

Variant 2-108897145-A-G is Benign according to our data. Variant chr2-108897145-A-G is described in ClinVar as [Benign]. Clinvar id is 5858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EDAR	NM_022336.4 linkuse as main transcript	c.1109T>C	p.Val370Ala	missense_variant	12/12	ENST00000258443.7
EDAR	XM_006712204.2 linkuse as main transcript	c.1205T>C	p.Val402Ala	missense_variant	11/11
RANBP2	XM_047445367.1 linkuse as main transcript	c.8370+124099A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7 linkuse as main transcript	c.1109T>C	p.Val370Ala	missense_variant	12/12	1	NM_022336.4	P1	Q9UNE0-1
EDAR	ENST00000376651.1 linkuse as main transcript	c.1205T>C	p.Val402Ala	missense_variant	11/11	2			Q9UNE0-2
EDAR	ENST00000409271.5 linkuse as main transcript	c.1205T>C	p.Val402Ala	missense_variant	12/12	2			Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.0698

AC:

10611

AN:

152038

Hom.:

2870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.885

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0536

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00693

Gnomad OTH

AF:

0.0750

GnomAD3 exomes

AF:

0.152

AC:

37782

AN:

248720

Hom.:

13017

AF XY:

0.127

AC XY:

17129

AN XY:

134726

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.919

Gnomad SAS exome

AF:

0.00903

Gnomad FIN exome

AF:

0.0542

Gnomad NFE exome

AF:

0.00801

Gnomad OTH exome

AF:

0.0952

GnomAD4 exome

AF:

0.0474

AC:

69266

AN:

1461676

Hom.:

20942

Cov.:

AF XY:

0.0439

AC XY:

31945

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00812

Gnomad4 AMR exome

AF:

0.483

Gnomad4 ASJ exome

AF:

0.0171

Gnomad4 EAS exome

AF:

0.840

Gnomad4 SAS exome

AF:

0.00939

Gnomad4 FIN exome

AF:

0.0559

Gnomad4 NFE exome

AF:

0.00522

Gnomad4 OTH exome

AF:

0.0658

GnomAD4 genome

AF:

0.0698

AC:

10621

AN:

152156

Hom.:

2877

Cov.:

AF XY:

0.0779

AC XY:

5796

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.273

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.885

Gnomad4 SAS

AF:

0.0166

Gnomad4 FIN

AF:

0.0536

Gnomad4 NFE

AF:

0.00693

Gnomad4 OTH

AF:

0.0743

Alfa

AF:

0.0399

Hom.:

3816

Bravo

AF:

0.0975

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.129

AC:

15663

Asia WGS

AF:

0.327

AC:

1136

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00522

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24752358, 19804850, 21916884, 23415220, 18704500, 23793515, 18561327, 22648185, 18493316, 18065779, 26105758, 26603699, 27487801, 32906216) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Non-syndromic oligodontia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Prosthodontics, Peking University School and Hospital of Stomatology

Apr 27, 2020

- -

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Hypohidrotic Ectodermal Dysplasia, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ectodermal dysplasia 10B, 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 16, 2018

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hair morphology 1, hair thickness

Other:1

association, no assertion criteria provided

literature only

OMIM

Aug 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

.;T;.

Eigen

Benign

0.031

Eigen_PC

Benign

0.089

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.57

.;T;T

MetaRNN

Benign

9.2e-7

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

.;N;.

MutationTaster

Benign

0.63

P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.60

N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.036

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.66

.;P;.

Vest4

0.12

MPC

0.49

ClinPred

0.044

GERP RS

5.6

Varity_R

0.15

gMVP

0.86

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