Genetic Variant EDN3:c.52+7G>C (chr20-59300871-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_207034.3(EDN3):c.52+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,610,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EDN3
NM_207034.3 splice_region, intron

Scores

Splicing: ADA: 0.0002718

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.653

Publications

0 publications found

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 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)

EDN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3 link	c.52+7G>C		splice_region_variant, intron_variant	Intron 1 of 4	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.52+7G>C		splice_region_variant, intron_variant	Intron 1 of 4	1	NM_207034.3	ENSP00000337128.2		P14138-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000845

AC:

AN:

236774

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000512

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457730

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.0000448

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111352

Other (OTH)

AF:

0.00

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41596

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.65

PromoterAI

0.039

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.022

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

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20-59300871-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over