rs863223424
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_001204.7(BMPR2):c.853-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,589,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001204.7 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.853-2A>G | splice_acceptor_variant | ENST00000374580.10 | |||
BMPR2 | XM_011511687.2 | c.853-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.853-2A>G | splice_acceptor_variant | 1 | NM_001204.7 | P1 | |||
BMPR2 | ENST00000374574.2 | c.853-2A>G | splice_acceptor_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000680 AC: 1AN: 147010Hom.: 0 Cov.: 31
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442196Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 718668
GnomAD4 genome ? AF: 0.00000680 AC: 1AN: 147010Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1AN XY: 71178
ClinVar
Submissions by phenotype
Pulmonary hypertension, primary, 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Center for Genomic Medicine, Kyoto University Graduate School of Medicine | Jul 11, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Pulmonary arterial hypertension Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 04, 2015 | c.853-2 A>G:IVS6-2 A>G in intron 6 of the BMPR2 gene (NM_001204.6). The c.853-2 A>G mutation has been reported in at least one individual with idiopathic PAH (Machado R et al., 2006). This mutation destroys the canonical splice acceptor site in intron 6 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay (Machado R et al., 2006). Other splice site mutations in the BMPR2 gene have been reported in association with PAH. Furthermore, the c.853-2 A>G mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.853-2 A>G in the BMPR2 gene is interpreted as a disease-causing mutation. This variant was found in PAH-PANCARD - |
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