2-108897145-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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:10O: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:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 rank	MANE	Protein	UniProt
EDAR	NM_022336.4 link	c.1109T>C	p.Val370Ala	missense_variant	Exon 12 of 12	ENST00000258443.7	NP_071731.1	Q9UNE0-1
EDAR	XM_006712204.2 link	c.1205T>C	p.Val402Ala	missense_variant	Exon 11 of 11		XP_006712267.1	Q9UNE0-2
RANBP2	XM_047445367.1 link	c.8370+124099A>G		intron_variant	Intron 24 of 24		XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDAR	ENST00000258443.7 link	c.1109T>C	p.Val370Ala	missense_variant	Exon 12 of 12	1	NM_022336.4	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1 link	c.1205T>C	p.Val402Ala	missense_variant	Exon 11 of 11	2		ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5 link	c.1205T>C	p.Val402Ala	missense_variant	Exon 12 of 12	2		ENSP00000386371.1	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:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24752358, 19804850, 21916884, 23415220, 18704500, 23793515, 18561327, 22648185, 18493316, 18065779, 26105758, 26603699, 27487801, 32906216) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Non-syndromic oligodontia

Pathogenic:1

Apr 27, 2020

Department of Prosthodontics, Peking University School and Hospital of Stomatology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Benign:1

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hypohidrotic Ectodermal Dysplasia, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ectodermal dysplasia 10B, 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 16, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hair morphology 1, hair thickness

Other:1

Aug 04, 2016

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;.

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