rs199476089
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5
The NM_004329.3(BMPR1A):c.1409T>C(p.Met470Thr) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M470I) has been classified as Uncertain significance.
Frequency
Consequence
NM_004329.3 missense
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 |
---|---|---|---|---|---|---|---|
BMPR1A | NM_004329.3 | c.1409T>C | p.Met470Thr | missense_variant | 12/13 | ENST00000372037.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR1A | ENST00000372037.8 | c.1409T>C | p.Met470Thr | missense_variant | 12/13 | 1 | NM_004329.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Juvenile polyposis syndrome Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 25, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 470 of the BMPR1A protein (p.Met470Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with juvenile polyposys syndrome (JPS) and/or clinical features of JPS (PMID: 12630959, 27696107). ClinVar contains an entry for this variant (Variation ID: 8236). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BMPR1A protein function. 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 20, 2023 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12630959, 37900118, 27696107]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2023 | The p.M470T variant (also known as c.1409T>C), located in coding exon 10 of the BMPR1A gene, results from a T to C substitution at nucleotide position 1409. The methionine at codon 470 is replaced by threonine, an amino acid with similar properties. This variant was reported in a Korean patient with a clinical diagnosis of juvenile polyposis syndrome who had approximately 300 polyps throughout her gastrointestinal tract (Kim IJ et al. Clin. Genet. 2003 Feb; 63(2):126-30). This variant has also been identified in probands diagnosed with adenomatous polyposis that underwent multigene panel testing (Ambry internal data; Rohlin A et al. Fam Cancer, 2017 04;16:195-203). Based on internal structural analysis, p.M470T is deleterious and moderately destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at