rs11570351

chr20-59324412-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_207034.3(EDN3):c.670G>A(p.Ala224Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,613,938 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A224V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: EDN3 NM_207034.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.368

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 -18 ACMG points.

• PM1: In a propeptide (size 120) in uniprot entity EDN3_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_207034.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006470144).
• BP6: Variant 20-59324412-G-A is Benign according to our data. Variant chr20-59324412-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 16647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-59324412-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00155 (235/152058) while in subpopulation AFR AF= 0.00528 (219/41472). AF 95% confidence interval is 0.00471. There are 3 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. 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.670G>A	p.Ala224Thr	missense_variant	5/5	ENST00000337938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDN3	ENST00000337938.7	c.670G>A	p.Ala224Thr	missense_variant	5/5	1	NM_207034.3	A2

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 151940 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251162 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135798

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000193 AC: 282 AN: 1461880 Hom.: 1 Cov.: 32 AF XY: 0.000171 AC XY: 124 AN XY: 727240

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00155 AC: 235 AN: 152058 Hom.: 3 Cov.: 32 AF XY: 0.00155 AC XY: 115 AN XY: 74308

Gnomad4 AFR AF: 0.00528

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000415 Hom.: 0

Bravo AF: 0.00156

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 07, 2015	p.Ala210Thr in exon 4 of EDN3: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (49/10242) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs 11570351). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Splice predictors are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in a patient with Hirschsprung disease in published literaure; however, this variant was also observed in the unaffected mother of this individual (Bidaud et al., 1997); This variant is associated with the following publications: (PMID: 9359047, 9359036, 9587491, 22995991) -

Waardenburg syndrome type 4B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hirschsprung disease, susceptibility to, 4 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	5.4
Dann	Benign	0.89
DEOGEN2	Benign	0.25	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.032	D;D;T
Polyphen		0.25	B;B;B
Vest4		0.14
MVP		0.86
MPC		0.17
ClinPred		0.0076	T
GERP RS		0.20
Varity_R		0.034
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs11570351; hg19: chr20-57899467; COSMIC: COSV61107311;