chr20-59300861-G-A

Position:

chr20-59300861-G-A

Variant summary

Our verdict is Benign. Variant got -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 made for transcript

Verdict is Benign. Variant got -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: {Likely_benign=1, Benign=6, Uncertain_significance=1}. 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDN3	NM_207034.3 linkuse as main transcript	c.49G>A	p.Ala17Thr	missense_variant	1/5	ENST00000337938.7	NP_996917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7 linkuse as main transcript	c.49G>A	p.Ala17Thr	missense_variant	1/5	1	NM_207034.3	ENSP00000337128	A2	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

GnomAD3 exomes

AF:

0.00333

AC:

797

AN:

239218

Hom.:

AF XY:

0.00267

AC XY:

352

AN XY:

131668

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 SAS exome

AF:

0.000460

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

Gnomad4 AMR exome

AF:

0.00990

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0212

Gnomad4 SAS exome

AF:

0.000592

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.00126

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

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000656

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

risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EDN3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	This variant is associated with the following publications: (PMID: 27535533, 9359047, 9587491, 20127975, 14633923, 30936914) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2016

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

MutationTaster

Benign

0.61

D;D;D;D;D

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

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