NM_207034.3:c.49G>A

Variant names:

• chr20-59300861-G-A
• rs11570255
• NM_207034.3:c.49G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 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 -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 VariationId is 16646.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD,SD,Unknown gene

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.49G>A	p.Ala17Thr	missense	Exon 1 of 5	NP_996917.1
	EDN3	NM_001424362.1		c.49G>A	p.Ala17Thr	missense	Exon 1 of 5	NP_001411291.1
	EDN3	NM_207033.3		c.49G>A	p.Ala17Thr	missense	Exon 1 of 4	NP_996916.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDN3	ENST00000337938.7	TSL:1 MANE Select	c.49G>A	p.Ala17Thr	missense	Exon 1 of 5	ENSP00000337128.2
	EDN3	ENST00000395654.3	TSL:1	c.49G>A	p.Ala17Thr	missense	Exon 1 of 4	ENSP00000379015.3
	EDN3	ENST00000311585.11	TSL:1	c.49G>A	p.Ala17Thr	missense	Exon 1 of 5	ENSP00000311854.7

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

GnomAD2 exomes AF: 0.00333 AC: 797 AN: 239218 AF XY: 0.00267

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 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

African (AFR) AF: 0.000389 AC: 13 AN: 33430

American (AMR) AF: 0.00990 AC: 442 AN: 44662

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

East Asian (EAS) AF: 0.0212 AC: 839 AN: 39664

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86154

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51522

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5328

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111558

Other (OTH) AF: 0.00126 AC: 76 AN: 60182

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

African (AFR) AF: 0.000890 AC: 37 AN: 41590

American (AMR) AF: 0.00327 AC: 50 AN: 15312

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

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000540 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Hirschsprung disease, susceptibility to, 4 (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.12
MVP		0.94
MPC		0.36
ClinPred		0.015	T
GERP RS		4.2
PromoterAI		0.012	Neutral
Varity_R		0.083
gMVP		0.33
Mutation Taster		=99/1	polymorphism

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