chr20-59301634-C-G
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_207034.3(EDN3):c.277C>G(p.Arg93Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
EDN3
NM_207034.3 missense
NM_207034.3 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 1.02
Publications
3 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 syndromeInheritance: AR Classification: DEFINITIVE Submitted by: G2P
- Waardenburg syndrome type 4BInheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia, G2P
- Waardenburg-Shah syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Hirschsprung disease, susceptibility to, 4Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_207034.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.944
PP5
Variant 20-59301634-C-G is Pathogenic according to our data. Variant chr20-59301634-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 16651.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727232 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461852
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727232
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111992
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Waardenburg syndrome type 4B Pathogenic:1
Jul 01, 2010
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;.;M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.;D;D
Sift4G
Pathogenic
D;D;D;.;D;D
Polyphen
D;.;D;.;D;D
Vest4
MutPred
Gain of catalytic residue at P89 (P = 0.0776);Gain of catalytic residue at P89 (P = 0.0776);Gain of catalytic residue at P89 (P = 0.0776);Gain of catalytic residue at P89 (P = 0.0776);Gain of catalytic residue at P89 (P = 0.0776);Gain of catalytic residue at P89 (P = 0.0776);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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