chr20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A

Position:

• chr20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM2 PM4 BP6_Very_Strong BS1

The ENST00000337938.7(EDN3):​c.167_190del​(p.Glu56_Glu63del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: EDN3 ENST00000337938.7 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0640

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000337938.7.
• BP6: Variant 20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A is Benign according to our data. Variant chr20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 504086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000716 (109/152144) while in subpopulation AFR AF= 0.00214 (89/41502). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDN3	NM_207034.3	c.167_190del	p.Glu56_Glu63del	inframe_deletion	2/5	ENST00000337938.7	NP_996917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7	c.167_190del	p.Glu56_Glu63del	inframe_deletion	2/5	1	NM_207034.3	ENSP00000337128	A2

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000257 AC: 64 AN: 249414 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135122

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461502 Hom.: 0 AF XY: 0.000142 AC XY: 103 AN XY: 727078

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000452

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000807 AC XY: 60 AN XY: 74388

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000654

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	- -

EDN3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749390209; hg19: chr20-57876553;