NM_207034.3:c.293C>T

Variant summary

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

The NM_207034.3(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 Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

EDN3
NM_207034.3 missense

Scores

14
3
2

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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a disulfide_bond (size 14) in uniprot entity EDN3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_207034.3
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 rank MANE Protein UniProt
EDN3NM_207034.3 linkc.293C>T p.Thr98Met missense_variant Exon 2 of 5 ENST00000337938.7 NP_996917.1 P14138-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDN3ENST00000337938.7 linkc.293C>T p.Thr98Met missense_variant Exon 2 of 5 1 NM_207034.3 ENSP00000337128.2 P14138-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Sensorineural hearing loss disorder Pathogenic:1
Sep 30, 2020
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
30
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
D
LIST_S2
Uncertain
0.92
.;D;D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Benign
1.7
L;L;L;.;.;L
PrimateAI
Uncertain
0.65
T
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
D
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.

Other links and lift over

hg19: chr20-57876705; COSMIC: COSV100284915; API