Variant 20-59301650-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The ENST00000337938.7(EDN3):c.293C>T(p.Thr98Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T98K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

EDN3
ENST00000337938.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.92

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a peptide Endothelin-3 (size 20) in uniprot entity EDN3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000337938.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-59301650-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 20-59301650-C-T is Pathogenic according to our data. Variant chr20-59301650-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984392.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-59301650-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDN3	NM_207034.3 linkuse as main transcript	c.293C>T	p.Thr98Met	missense_variant	2/5	ENST00000337938.7	NP_996917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDN3	ENST00000337938.7 linkuse as main transcript	c.293C>T	p.Thr98Met	missense_variant	2/5	1	NM_207034.3	ENSP00000337128	A2	P14138-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Sensorineural hearing loss disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences

Sep 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;D;.;D;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D;D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.7

L;L;L;.;.;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.5

D;D;D;.;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D;D;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;.;D;D

Polyphen

1.0

D;.;D;.;D;D

Vest4

0.85

MutPred

0.68

Loss of phosphorylation at T98 (P = 0.0382);Loss of phosphorylation at T98 (P = 0.0382);Loss of phosphorylation at T98 (P = 0.0382);Loss of phosphorylation at T98 (P = 0.0382);Loss of phosphorylation at T98 (P = 0.0382);Loss of phosphorylation at T98 (P = 0.0382);

MVP

0.98

MPC

0.62

ClinPred

0.99

GERP RS

4.8

Varity_R

0.84

gMVP

0.83

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over