rs151195196

Positions:

chr2-108930972-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022336.4(EDAR):c.43G>A(p.Val15Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,920 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 4 hom. )

Consequence

EDAR
NM_022336.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: -0.0180

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0111916065).

BP6

Variant 2-108930972-C-T is Benign according to our data. Variant chr2-108930972-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463880.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00232 (354/152276) while in subpopulation AFR AF= 0.00815 (339/41570). AF 95% confidence interval is 0.00744. There are 1 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EDAR	NM_022336.4 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	2/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	2/11		XP_006712267.1
RANBP2	XM_047445367.1 linkuse as main transcript	c.8370+157926C>T		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	2/12	1	NM_022336.4	ENSP00000258443	P1	Q9UNE0-1
EDAR	ENST00000376651.1 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	2/11	2		ENSP00000365839		Q9UNE0-2
EDAR	ENST00000409271.5 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	3/12	2		ENSP00000386371		Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00815

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000649

AC:

163

AN:

251274

Hom.:

AF XY:

0.000552

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00837

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461644

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00842

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.00232

AC:

354

AN:

152276

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00815

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.00261

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33943035, 32906216) -

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

Sep 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

2.5

DANN

Benign

0.93

DEOGEN2

Benign

0.28

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.64

.;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

0.020

N;N;N

REVEL

Benign

0.057

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.091

.;B;.

Vest4

0.17

MVP

0.57

MPC

0.24

ClinPred

0.0035

GERP RS

-0.035

Varity_R

0.026

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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