ENST00000311585.11:c.-248G>A

Variant names:

• chr20-59300565-G-A
• rs542818479
• ENST00000311585.11:c.-248G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000311585.11(EDN3):​c.-248G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00848 in 531,540 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (20 hom.)
• Consequence: EDN3 ENST00000311585.11 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.749
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3	c.-248G>A		upstream_gene_variant		ENST00000337938.7	NP_996917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7	c.-248G>A		upstream_gene_variant		1	NM_207034.3	ENSP00000337128.2

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152228 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00950

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00900 AC: 3413 AN: 379196 Hom.: 20 Cov.: 3 AF XY: 0.00924 AC XY: 1844 AN XY: 199474

African (AFR) AF: 0.00178 AC: 14 AN: 7862

American (AMR) AF: 0.00897 AC: 115 AN: 12818

Ashkenazi Jewish (ASJ) AF: 0.00415 AC: 48 AN: 11554

East Asian (EAS) AF: 0.00 AC: 0 AN: 24412

South Asian (SAS) AF: 0.00880 AC: 325 AN: 36946

European-Finnish (FIN) AF: 0.0122 AC: 334 AN: 27332

Middle Eastern (MID) AF: 0.00583 AC: 10 AN: 1714

European-Non Finnish (NFE) AF: 0.0101 AC: 2373 AN: 234150

Other (OTH) AF: 0.00866 AC: 194 AN: 22408

GnomAD4 genome AF: 0.00720 AC: 1097 AN: 152344 Hom.: 7 Cov.: 32 AF XY: 0.00691 AC XY: 515 AN XY: 74506

African (AFR) AF: 0.00188 AC: 78 AN: 41586

American (AMR) AF: 0.00706 AC: 108 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4830

European-Finnish (FIN) AF: 0.00950 AC: 101 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 712 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00956 Hom.: 1

Bravo AF: 0.00697

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 21, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23840513) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EDN3: BS1, BS2 -

not specified Benign:1

Aug 07, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hirschsprung Disease, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.98
PhyloP100		0.75
PromoterAI		-0.14	Neutral
Mutation Taster		=300/0	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: rs542818479; hg19: chr20-57875620;