rs187049336

Variant names:

• chr20-59321077-G-A
• rs187049336
• NM_207034.3:c.426G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-59321077-G-A
• chr20-59321077-G-C
• chr20-59321077-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_207034.3(EDN3):​c.426G>A​(p.Ala142Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,614,220 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (5 hom.)
• Consequence: EDN3 NM_207034.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-59321077-G-A is Benign according to our data. Variant chr20-59321077-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 339124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3	c.426G>A	p.Ala142Ala	synonymous_variant	Exon 3 of 5	ENST00000337938.7	NP_996917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7	c.426G>A	p.Ala142Ala	synonymous_variant	Exon 3 of 5	1	NM_207034.3	ENSP00000337128.2

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251482 AF XY: 0.000912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00946

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000339 AC: 495 AN: 1461892 Hom.: 5 Cov.: 32 AF XY: 0.000359 AC XY: 261 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00526 AC: 209 AN: 39700

South Asian (SAS) AF: 0.00202 AC: 174 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1112010

Other (OTH) AF: 0.000944 AC: 57 AN: 60396

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000314

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala142Ala in exon 3 of EDN3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.9% (74/8652) of E ast Asian chromosomes and 0.2% (38/16512) of South Asian chromsomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNPdbSNP rs1870 49336). -

Waardenburg syndrome type 4B;C3150975:Hirschsprung disease, susceptibility to, 4 Benign:1

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hirschsprung disease, susceptibility to, 4 Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		-1.5
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs187049336; hg19: chr20-57896132; COSMIC: COSV61107891;