Genetic Variant NM_207034.3:c.167_190delAGACTGTGGCTGGCCCTGGCGAGG (chr20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM2PM4BP6_Very_Strong

The NM_207034.3(EDN3):c.167_190delAGACTGTGGCTGGCCCTGGCGAGG(p.Glu56_Glu63del) variant causes a disruptive 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
NM_207034.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0640

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_207034.3.

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].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3 link	c.167_190delAGACTGTGGCTGGCCCTGGCGAGG	p.Glu56_Glu63del	disruptive_inframe_deletion	Exon 2 of 5	ENST00000337938.7	NP_996917.1	P14138-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7 link	c.167_190delAGACTGTGGCTGGCCCTGGCGAGG	p.Glu56_Glu63del	disruptive_inframe_deletion	Exon 2 of 5	1	NM_207034.3	ENSP00000337128.2		P14138-1

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

109

AN:

152028

Hom.:

Cov.:

show subpopulations

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:

AN:

249414

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135122

show subpopulations

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.:

AF XY:

0.000142

AC XY:

103

AN XY:

727078

show subpopulations

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.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

74388

show subpopulations

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.:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EDN3-related disorder

Benign:1

Mar 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name

Calibrated prediction

Score

Prediction

Splicing

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