chr20-59301425-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207034.3(EDN3):​c.68C>G​(p.Ser23Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EDN3
NM_207034.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.711

Publications

0 publications found
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 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14404464).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDN3NM_207034.3 linkc.68C>G p.Ser23Cys 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.68C>G p.Ser23Cys missense_variant Exon 2 of 5 1 NM_207034.3 ENSP00000337128.2 P14138-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459630
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726196
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51434
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5578
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60362
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
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
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.68C>G (p.S23C) alteration is located in exon 2 (coding exon 2) of the EDN3 gene. This alteration results from a C to G substitution at nucleotide position 68, causing the serine (S) at amino acid position 23 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.48
T;.;T;.;T;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.052
N
LIST_S2
Benign
0.69
.;T;T;T;T;T
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.14
T;T;T;T;T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
0.0
N;N;N;.;.;N
PhyloP100
0.71
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.1
N;N;N;.;N;N
REVEL
Benign
0.22
Sift
Benign
0.056
T;D;T;.;D;T
Sift4G
Uncertain
0.0070
D;D;D;.;D;D
Polyphen
0.98
D;.;D;.;D;D
Vest4
0.29
MutPred
0.29
Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);
MVP
0.86
MPC
0.13
ClinPred
0.17
T
GERP RS
3.8
PromoterAI
0.017
Neutral
Varity_R
0.15
gMVP
0.22
Mutation Taster
=92/8
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

Publications

Other links and lift over

dbSNP: rs1186875427; hg19: chr20-57876480; API