20-59300861-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_207034.3(EDN3):c.49G>A(p.Ala17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,610,930 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (13 hom.)
• Consequence: EDN3 NM_207034.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 2.05

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008144647).
• BP6: Variant 20-59300861-G-A is Benign according to our data. Variant chr20-59300861-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16646.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=1}. Variant chr20-59300861-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00125 (191/152364) while in subpopulation EAS AF= 0.0193 (100/5176). AF 95% confidence interval is 0.0163. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDN3	NM_207034.3	c.49G>A	p.Ala17Thr	missense_variant	1/5	ENST00000337938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDN3	ENST00000337938.7	c.49G>A	p.Ala17Thr	missense_variant	1/5	1	NM_207034.3	A2

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00333 AC: 797 AN: 239218 Hom.: 5 AF XY: 0.00267 AC XY: 352 AN XY: 131668

Gnomad AFR exome AF: 0.000983

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0196

Gnomad SAS exome AF: 0.000460

Gnomad FIN exome AF: 0.0000498

Gnomad NFE exome AF: 0.0000750

Gnomad OTH exome AF: 0.00273

GnomAD4 exome AF: 0.00102 AC: 1486 AN: 1458566 Hom.: 13 Cov.: 31 AF XY: 0.000947 AC XY: 687 AN XY: 725646

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00990

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0212

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74514

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000656 Hom.: 1

Bravo AF: 0.00207

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00304 AC: 367

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hirschsprung disease, susceptibility to, 4 Uncertain:1 Benign:2 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Ala17Thr variant in EDN3 has been identified in an individual with Hirschsprung disease (PMID: 9587491), and has been identified in >2% of East Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Hirschsprung disease. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	This variant is associated with the following publications: (PMID: 27535533, 9359047, 9587491, 20127975, 14633923, 30936914) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EDN3: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2016

p.Ala17Thr in exon 1 of EDN3: This variant is not expected to have clinical sign ificance because it has been identified in 2.4% (185/7748) of East Asian chromos omes including 4 homozygotes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs11570255). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;T;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.64	D
MetaRNN	Benign	0.0081	T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L;L;L;.;.;L
MutationTaster	Benign	0.61	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;N;N;.;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T;T;T;.;T;T
Sift4G	Benign	0.14	T;T;T;.;T;T
Polyphen		0.98	D;.;D;.;D;D
Vest4		0.12
MVP		0.94
MPC		0.36
ClinPred		0.015	T
GERP RS		4.2
Varity_R		0.083
gMVP		0.33

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: rs11570255; hg19: chr20-57875916; COSMIC: COSV61108118;