rs144565124
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001122659.3(EDNRB):c.1285G>A(p.Gly429Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,611,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
EDNRB
NM_001122659.3 missense
NM_001122659.3 missense
Scores
2
8
7
Clinical Significance
Conservation
PhyloP100: 5.88
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15830201).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EDNRB | NM_001122659.3 | c.1285G>A | p.Gly429Arg | missense_variant | 7/7 | ENST00000646607.2 | |
EDNRB-AS1 | NR_103853.1 | n.1695-9448C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EDNRB | ENST00000646607.2 | c.1285G>A | p.Gly429Arg | missense_variant | 7/7 | NM_001122659.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000198 AC: 30AN: 151896Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000124 AC: 31AN: 249884Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 135088
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GnomAD4 exome AF: 0.000134 AC: 195AN: 1459948Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 100AN XY: 726268
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GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152014Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 11, 2015 | The p.Gly519Arg variant in EDNRB has not been previously reported in individuals with hearing loss or Waardenburg syndrome, but has been identified in 6/65674 E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs144565124). Although this variant has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical signi ficance of the Gly519Arg variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2019 | Variant summary: EDNRB c.1285G>A (p.Gly429Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 275528 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1285G>A in individuals affected with Waardenburg syndrome type 4A and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2022 | The c.1285G>A (p.G429R) alteration is located in exon 8 (coding exon 7) of the EDNRB gene. This alteration results from a G to A substitution at nucleotide position 1285, causing the glycine (G) at amino acid position 429 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hirschsprung Disease, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 429 of the EDNRB protein (p.Gly429Arg). This variant is present in population databases (rs144565124, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EDNRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 228662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
ABCD syndrome;C1838564:Hirschsprung disease, susceptibility to, 2;C1848519:Waardenburg syndrome type 4A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Waardenburg syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;.;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;.;.
REVEL
Benign
Sift
Uncertain
D;.;.;D;.;.
Sift4G
Uncertain
D;.;.;D;.;.
Polyphen
P;D;D;D;D;D
Vest4
MutPred
0.23
.;Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);
MVP
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T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at