rs11570351

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_207034.3(EDN3):c.670G>A(p.Ala224Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,613,938 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A224V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

EDN3
NM_207034.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.368

Publications

11 publications found

Variant links:

Genes affected

EDN3 (HGNC:3178): (endothelin 3) The protein encoded by this gene is a member of the endothelin family. Endothelins are endothelium-derived vasoactive peptides involved in a variety of biological functions. The active form of this protein is a 21 amino acid peptide processed from the precursor protein. The active peptide is a ligand for endothelin receptor type B (EDNRB). The interaction of this endothelin with EDNRB is essential for development of neural crest-derived cell lineages, such as melanocytes and enteric neurons. Mutations in this gene and EDNRB have been associated with Hirschsprung disease (HSCR) and Waardenburg syndrome (WS), which are congenital disorders involving neural crest-derived cells. Altered expression of this gene is implicated in tumorigenesis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

EDN3 Gene-Disease associations (from GenCC):

Waardenburg syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Waardenburg syndrome type 4B
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia, G2P
Waardenburg-Shah syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease, susceptibility to, 4
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

EDN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006470144).

BP6

Variant 20-59324412-G-A is Benign according to our data. Variant chr20-59324412-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 16647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3 link	c.670G>A	p.Ala224Thr	missense_variant	Exon 5 of 5	ENST00000337938.7	NP_996917.1	P14138-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7 link	c.670G>A	p.Ala224Thr	missense_variant	Exon 5 of 5	1	NM_207034.3	ENSP00000337128.2		P14138-1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00510

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000394

AC:

AN:

251162

AF XY:

0.000287

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000193

AC:

282

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00511

AC:

171

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1112012

Other (OTH)

AF:

0.000563

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00155

AC:

235

AN:

152058

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

115

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00528

AC:

219

AN:

41472

American (AMR)

AF:

0.000458

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68004

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000727

Hom.:

Bravo

AF:

0.00156

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000469

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 07, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala210Thr in exon 4 of EDN3: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (49/10242) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs 11570351). -

Aug 11, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 25, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Splice predictors are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in a patient with Hirschsprung disease in published literaure; however, this variant was also observed in the unaffected mother of this individual (Bidaud et al., 1997); This variant is associated with the following publications: (PMID: 9359047, 9359036, 9587491, 22995991) -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Waardenburg syndrome type 4B

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hirschsprung disease, susceptibility to, 4

Other:1

Jul 01, 1997

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

5.4

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.43

.;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

-0.37

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.28

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.032

D;D;T

Polyphen

0.25

B;B;B

Vest4

0.14

MVP

0.86

MPC

0.17

ClinPred

0.0076

GERP RS

0.20

Varity_R

0.034

gMVP

0.11

Mutation Taster

=11/89

disease causing

(source)

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

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rs11570351

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over