20-59322388-G-GA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The NM_207034.3(EDN3):c.565dup(p.Thr189AsnfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,168 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: EDN3 NM_207034.3 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:6
• Conservation: PhyloP100: -1.53

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.22 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 20-59322388-G-GA is Benign according to our data. Variant chr20-59322388-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 227351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (421/152310) while in subpopulation NFE AF= 0.00354 (241/68014). AF 95% confidence interval is 0.00318. There are 0 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDN3	NM_207034.3	c.565dup	p.Thr189AsnfsTer10	frameshift_variant	4/5	ENST00000337938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDN3	ENST00000337938.7	c.565dup	p.Thr189AsnfsTer10	frameshift_variant	4/5	1	NM_207034.3	A2

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00213 AC: 535 AN: 251422 Hom.: 3 AF XY: 0.00210 AC XY: 285 AN XY: 135892

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00587

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00260 AC: 3805 AN: 1461858 Hom.: 9 Cov.: 32 AF XY: 0.00257 AC XY: 1871 AN XY: 727230

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00657

Gnomad4 NFE exome AF: 0.00281

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00276 AC: 421 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74484

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.000948

Bravo AF: 0.00235

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	Frameshift variant predicted to result in protein truncation as the last 50 amino acids are replaced with 9 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19556619, 8696331, 20127975, 30096381) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -

Aganglionic megacolon Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Human Genomics Unit, Institute for molecular medicine Finland (FIMM)

-

- -

Congenital central hypoventilation Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 1996

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2017

p.Thr189fs in exon 4 of EDN3: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (157/25790) of Finnish chromosom es including 2 homozygotes, and 0.3% (381/126686) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 11570344). The variant has been reported in an individual with congenital centra l hypoventilation syndrome and an individual with Hirschsprung disease; however, the variant did not segregate with disease in an affected sibling while several unaffected family members harbored this variant. In addition, in vitro function al analysis indicated no effect on protein expression and the authors pointed ou t that the variant occurs in a region near the 3' end that is cleaved off in the active form of the protein (Bolk 1996, Sanchez-Mejias 2009). In summary, this variant is benign based on its frequency and lack of evidence to support pathoge nicity. -

EDN3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hirschsprung Disease, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Waardenburg syndrome type 4B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs11570344; hg19: chr20-57897443;