rs876657805
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000377211.8(EDNRB):c.7A>T(p.Lys3Ter) variant causes a stop gained change involving the alteration of a non-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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
EDNRB
ENST00000377211.8 stop_gained
ENST00000377211.8 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 0.668
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 Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 73 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDNRB | NM_001201397.1 | c.7A>T | p.Lys3Ter | stop_gained | 1/8 | ||
EDNRB | NM_000115.5 | c.-51-985A>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDNRB | ENST00000377211.8 | c.7A>T | p.Lys3Ter | stop_gained | 1/8 | 1 | |||
EDNRB | ENST00000646948.1 | c.-51-985A>T | intron_variant | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2015 | The p.Lys3X variant in EDNRB (NM_001201387.1) has not been previously reported i n individuals with hearing loss, type 4 Waardenburg syndrome, or Hirschsprung di sease, and was absent from large population studies. This nonsense variant affec ts the coding region of only one of four transcript isoforms of the EDNRB gene a nd exon 1 of this isoform lies in either intergenic or intronic regions of the o ther EDNRB isoforms. In addition, pathogenic variants in exon 1 of this transcri pt have not been reported in affected individuals and this exon is enriched for loss of function variants compared with other exons of this gene in the control population (ExAC, http://exac.broadinstitute.org). This suggests that this exon and/or transcript may not be critical for a functional protein; however, additio nal studies are needed to confirm this. In summary, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at