20-59300769-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_207034.3(EDN3):c.-44C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,591,592 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (4 hom.)
• Consequence: EDN3 NM_207034.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.129

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-59300769-C-T is Benign according to our data. Variant chr20-59300769-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 339120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000643 (98/152358) while in subpopulation SAS AF= 0.00103 (5/4834). AF 95% confidence interval is 0.000408. There are 2 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDN3	NM_207034.3	c.-44C>T		5_prime_UTR_variant	1/5	ENST00000337938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDN3	ENST00000337938.7	c.-44C>T		5_prime_UTR_variant	1/5	1	NM_207034.3	A2

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00111 AC: 232 AN: 209916 Hom.: 0 AF XY: 0.00114 AC XY: 132 AN XY: 115468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000675 AC: 972 AN: 1439234 Hom.: 4 Cov.: 30 AF XY: 0.000739 AC XY: 528 AN XY: 714834

Gnomad4 AFR exome AF: 0.0000913

Gnomad4 AMR exome AF: 0.000164

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000224

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74520

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hirschsprung disease, susceptibility to, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	9.4
Dann	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs368814466; hg19: chr20-57875824;