20-59301185-G-T

Variant names:

• chr20-59301185-G-T
• rs149214
• NM_207034.3:c.53-225G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_207034.3(EDN3):​c.53-225G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,290 control chromosomes in the GnomAD database, including 1,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1988 hom., cov: 33)
• Consequence: EDN3 NM_207034.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-59301185-G-T is Benign according to our data. Variant chr20-59301185-G-T is described in ClinVar as [Benign]. Clinvar id is 1178568.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3	c.53-225G>T		intron_variant	Intron 1 of 4	ENST00000337938.7	NP_996917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7	c.53-225G>T		intron_variant	Intron 1 of 4	1	NM_207034.3	ENSP00000337128.2

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20848 AN: 152172 Hom.: 1966 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.0793

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0815

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.0963

Gnomad OTH AF: 0.136

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.137 AC: 20920 AN: 152290 Hom.: 1988 Cov.: 33 AF XY: 0.134 AC XY: 9959 AN XY: 74470

African (AFR) AF: 0.262 AC: 10883 AN: 41530

American (AMR) AF: 0.0792 AC: 1212 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 324 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.115 AC: 554 AN: 4830

European-Finnish (FIN) AF: 0.0815 AC: 865 AN: 10614

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0963 AC: 6552 AN: 68030

Other (OTH) AF: 0.135 AC: 285 AN: 2112

Alfa AF: 0.106 Hom.: 600

Bravo AF: 0.141

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: 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	-0.89
CADD	Benign	4.4
DANN	Benign	0.68
PhyloP100		0.28
PromoterAI		0.028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149214; hg19: chr20-57876240;