20-59300861-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_207034.3(EDN3):c.49G>A(p.Ala17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,610,930 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 13 hom. )

Consequence

EDN3
NM_207034.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 2.05

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008144647).

BP6

Variant 20-59300861-G-A is Benign according to our data. Variant chr20-59300861-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16646.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=6}. Variant chr20-59300861-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00125 (191/152364) while in subpopulation EAS AF = 0.0193 (100/5176). AF 95% confidence interval is 0.0163. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3 link	c.49G>A	p.Ala17Thr	missense_variant	Exon 1 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.49G>A	p.Ala17Thr	missense_variant	Exon 1 of 5	1	NM_207034.3	ENSP00000337128.2		P14138-1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0195

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00333

AC:

797

AN:

239218

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.000983

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0196

Gnomad FIN exome

AF:

0.0000498

Gnomad NFE exome

AF:

0.0000750

Gnomad OTH exome

AF:

0.00273

GnomAD4 exome

AF:

0.00102

AC:

1486

AN:

1458566

Hom.:

Cov.:

AF XY:

0.000947

AC XY:

687

AN XY:

725646

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

AC:

AN:

33430

Gnomad4 AMR exome

AF:

0.00990

AC:

442

AN:

44662

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26066

Gnomad4 EAS exome

AF:

0.0212

AC:

839

AN:

39664

Gnomad4 SAS exome

AF:

0.000592

AC:

AN:

86154

Gnomad4 FIN exome

AF:

0.0000194

AC:

AN:

51522

Gnomad4 NFE exome

AF:

0.0000567

AC:

AN:

1111558

Gnomad4 Remaining exome

AF:

0.00126

AC:

AN:

60182

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00125

AC:

191

AN:

152364

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000890

AC:

0.000889637

AN:

0.000889637

Gnomad4 AMR

AF:

0.00327

AC:

0.00326541

AN:

0.00326541

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.0193

AC:

0.0193199

AN:

0.0193199

Gnomad4 SAS

AF:

0.000414

AC:

0.00041425

AN:

0.00041425

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000146977

AN:

0.0000146977

Gnomad4 OTH

AF:

0.000473

AC:

0.000473037

AN:

0.000473037

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000540

Hom.:

Bravo

AF:

0.00207

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00304

AC:

367

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hirschsprung disease, susceptibility to, 4

Uncertain:1Benign:2Other:1

Jul 01, 1997

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Ala17Thr variant in EDN3 has been identified in an individual with Hirschsprung disease (PMID: 9587491), and has been identified in >2% of East Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Hirschsprung disease. -

not provided

Benign:4

Nov 09, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EDN3: BS1, BS2 -

Sep 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27535533, 9359047, 9587491, 20127975, 14633923, 30936914) -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala17Thr in exon 1 of EDN3: This variant is not expected to have clinical sign ificance because it has been identified in 2.4% (185/7748) of East Asian chromos omes including 4 homozygotes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs11570255). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.;T;.;T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.70

.;T;T;T;T;T

MetaRNN

Benign

0.0081

T;T;T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.8

L;L;L;.;.;L

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.6

N;N;N;.;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.12

T;T;T;.;T;T

Sift4G

Benign

0.14

T;T;T;.;T;T

Polyphen

0.98

D;.;D;.;D;D

Vest4

0.12

MVP

0.94

MPC

0.36

ClinPred

0.015

GERP RS

4.2

Varity_R

0.083

gMVP

0.33

Mutation Taster

=99/1

polymorphism

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