20-59300989-C-T

Variant names:

• chr20-59300989-C-T
• rs155001
• NM_207034.3:c.52+125C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207034.3(EDN3):​c.52+125C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,152,400 control chromosomes in the GnomAD database, including 2,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (534 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2011 hom.)
• Consequence: EDN3 NM_207034.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.247
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 20-59300989-C-T is Benign according to our data. Variant chr20-59300989-C-T is described in ClinVar as [Benign]. Clinvar id is 1291826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDN3	NM_207034.3	c.52+125C>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.52+125C>T		intron_variant	Intron 1 of 4	1	NM_207034.3	ENSP00000337128.2

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 11328 AN: 152144 Hom.: 532 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0794

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0600

Gnomad OTH AF: 0.0884

GnomAD4 exome AF: 0.0583 AC: 58313 AN: 1000136 Hom.: 2011 AF XY: 0.0593 AC XY: 29801 AN XY: 502862

African (AFR) AF: 0.126 AC: 2961 AN: 23428

American (AMR) AF: 0.0371 AC: 1097 AN: 29558

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 1308 AN: 20476

East Asian (EAS) AF: 0.000296 AC: 10 AN: 33770

South Asian (SAS) AF: 0.0808 AC: 5299 AN: 65548

European-Finnish (FIN) AF: 0.0487 AC: 1595 AN: 32758

Middle Eastern (MID) AF: 0.106 AC: 341 AN: 3218

European-Non Finnish (NFE) AF: 0.0574 AC: 42863 AN: 746836

Other (OTH) AF: 0.0637 AC: 2839 AN: 44544

GnomAD4 genome AF: 0.0745 AC: 11341 AN: 152264 Hom.: 534 Cov.: 33 AF XY: 0.0733 AC XY: 5460 AN XY: 74460

African (AFR) AF: 0.125 AC: 5193 AN: 41552

American (AMR) AF: 0.0467 AC: 715 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3472

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.0799 AC: 385 AN: 4820

European-Finnish (FIN) AF: 0.0431 AC: 457 AN: 10614

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0600 AC: 4080 AN: 68010

Other (OTH) AF: 0.0875 AC: 185 AN: 2114

Alfa AF: 0.0542 Hom.: 103

Bravo AF: 0.0750

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 17, 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	-0.73
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		0.25
PromoterAI		-0.033	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: rs155001; hg19: chr20-57876044;