20-59300860-C-T

Variant names:

• chr20-59300860-C-T
• rs550205592
• NM_207034.3:c.48C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_207034.3(EDN3):​c.48C>T​(p.Ala16Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,611,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: EDN3 NM_207034.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.09
• Publications: 0 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 type 4B

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• Waardenburg syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Waardenburg-Shah syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease, susceptibility to, 4

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 20-59300860-C-T is Benign according to our data. Variant chr20-59300860-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1900028.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.09 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207034.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDN3	NM_207034.3	MANE Select	c.48C>T	p.Ala16Ala	synonymous	Exon 1 of 5	NP_996917.1	P14138-1
	EDN3	NM_001424362.1		c.48C>T	p.Ala16Ala	synonymous	Exon 1 of 5	NP_001411291.1
	EDN3	NM_207033.3		c.48C>T	p.Ala16Ala	synonymous	Exon 1 of 4	NP_996916.1	P14138-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDN3	ENST00000337938.7	TSL:1 MANE Select	c.48C>T	p.Ala16Ala	synonymous	Exon 1 of 5	ENSP00000337128.2	P14138-1
	EDN3	ENST00000395654.3	TSL:1	c.48C>T	p.Ala16Ala	synonymous	Exon 1 of 4	ENSP00000379015.3	P14138-2
	EDN3	ENST00000311585.11	TSL:1	c.48C>T	p.Ala16Ala	synonymous	Exon 1 of 5	ENSP00000311854.7	P14138-3

Frequencies

GnomAD3 genomes AF: 0.0000722 AC: 11 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

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: 0.0000251 AC: 6 AN: 239306 AF XY: 0.0000152

Gnomad AFR exome AF: 0.000351

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458674 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725720

African (AFR) AF: 0.000239 AC: 8 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111574

Other (OTH) AF: 0.00 AC: 0 AN: 60190

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152388 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74518

African (AFR) AF: 0.000240 AC: 10 AN: 41594

American (AMR) AF: 0.0000653 AC: 1 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.3
DANN	Benign	0.96
PhyloP100		-2.1
PromoterAI		-0.044	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs550205592; hg19: chr20-57875915;