rs104894388
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_001122659.3(EDNRB):c.548C>G(p.Ala183Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
EDNRB
NM_001122659.3 missense
NM_001122659.3 missense
Scores
4
7
6
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
EDNRB (HGNC:3180): (endothelin receptor type B) The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001122659.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.786
PP5
?
Variant 13-77903543-G-C is Pathogenic according to our data. Variant chr13-77903543-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-77903543-G-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDNRB | NM_001122659.3 | c.548C>G | p.Ala183Gly | missense_variant | 2/7 | ENST00000646607.2 | |
EDNRB-AS1 | NR_103853.1 | n.1695-4149G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDNRB | ENST00000646607.2 | c.548C>G | p.Ala183Gly | missense_variant | 2/7 | NM_001122659.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Waardenburg syndrome type 4A Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1995 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;.;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;.;.;N;.;.;.;.;.
REVEL
Uncertain
Sift
Benign
D;.;.;D;.;.;.;.;.
Sift4G
Benign
T;.;.;T;.;T;.;.;.
Polyphen
B;B;B;B;B;P;B;.;.
Vest4
MutPred
0.77
.;Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);Loss of ubiquitination at K182 (P = 0.1231);.;Loss of ubiquitination at K182 (P = 0.1231);
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