rs869025367
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_001204.7(BMPR2):c.1276G>A(p.Gly426Arg) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G426G) has been classified as Likely benign.
Frequency
Consequence
NM_001204.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.1276G>A | p.Gly426Arg | missense_variant, splice_region_variant | 9/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.1276G>A | p.Gly426Arg | missense_variant, splice_region_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.1276G>A | p.Gly426Arg | missense_variant, splice_region_variant | 9/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.1276G>A | p.Gly426Arg | missense_variant, splice_region_variant | 9/12 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Primary pulmonary hypertension Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 03, 2017 | This sequence change replaces glycine with arginine at codon 426 of the BMPR2 protein (p.Gly426Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 9 of the BMPR2 coding sequence, which is part of the consensus splice site for this exon. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BMPR2-related disease. However, a different variant affecting the same nucleotide and resulting in the same amino acid change (c.1276G>C (p.Gly426Arg)) has been reported in the literature in an individual affected with heritable pulmonary arterial hypertension (PMID: 26387786). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at