rs1085307216
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001204.7(BMPR2):c.353G>A(p.Cys118Tyr) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C118W) has been classified as Pathogenic.
Frequency
Consequence
NM_001204.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.353G>A | p.Cys118Tyr | missense_variant | 3/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.353G>A | p.Cys118Tyr | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.353G>A | p.Cys118Tyr | missense_variant | 3/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.353G>A | p.Cys118Tyr | missense_variant | 3/12 | 2 | |||
BMPR2 | ENST00000479069.1 | n.260G>A | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 04, 2019 | The BMPR2 c.353G>A; p.Cys118Tyr variant (rs1085307216) is reported in the literature in several individuals affected with pulmonary arterial hypertension (PAH) (Machado 2006, Pfarr 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 118 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other amino acid substitutions at this codon and the adjacent cysteine (p.Cys117Tyr, p.Cys118Trp, p.Cys118Ser) have been reported in individuals with PAH and are considered disease-causing (Barozzi 2019, Machado 2006). Further, functional assays indicate that several of these other substitutions (p.Cys117Tyr and p.Cys118Trp) are mislocalized in the cell and exhibit signaling defects (Rudarakanchana 2002, Sobolewski 2008). Based on available information, the p.Cys118Tyr variant is considered to be likely pathogenic. References: Barozzi C et al. A Combined Targeted and Whole Exome Sequencing Approach Identified Novel Candidate Genes Involved in Heritable Pulmonary Arterial Hypertension. Sci Rep. 2019 Jan 24;9(1):753. Machado RD et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006 Feb;27(2):121-32. Pfarr N et al. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respir Res. 2011 Jul 29;12:99. Rudarakanchana N et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet. 2002 Jun 15;11(13):1517-25. Sobolewski A et al. Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. Hum Mol Genet. 2008 Oct 15;17(20):3180-90. - |
Pulmonary hypertension, primary, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension Other:1
not provided, no classification provided | literature only | Wendy Chung Laboratory, Columbia University Medical Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at