rs786201991
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The ENST00000372037.8(BMPR1A):āc.1379T>Cā(p.Met460Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. M460I) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000372037.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BMPR1A | NM_004329.3 | c.1379T>C | p.Met460Thr | missense_variant | 12/13 | ENST00000372037.8 | NP_004320.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BMPR1A | ENST00000372037.8 | c.1379T>C | p.Met460Thr | missense_variant | 12/13 | 1 | NM_004329.3 | ENSP00000361107 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251492Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135920
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Juvenile polyposis syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 460 of the BMPR1A protein (p.Met460Thr). This variant is present in population databases (rs758309022, gnomAD 0.007%). This missense change has been observed in individual(s) with BMPR1A-related conditions (PMID: 25860647). ClinVar contains an entry for this variant (Variation ID: 185192). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 16, 2023 | This missense variant replaces methionine with threonine at codon 460 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with a tubular adenoma, a hyperplastic polyp and a rectal neuroendocrine tumour (PMID: 25860647). This variant has been identified in 8/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 08, 2023 | This missense variant replaces methionine with threonine at codon 460 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with a tubular adenoma, a hyperplastic polyp and a rectal neuroendocrine tumour (PMID: 25860647). This variant has been identified in 8/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Polyposis syndrome, hereditary mixed, 2;C1868081:Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2016 | This variant is denoted BMPR1A c.1379T>C at the cDNA level, p.Met460Thr (M460T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was reported in an individual with a history of tubular adenoma, hyperplastic polyp, and rectal neuroendocrine tumor, however, the variant did not segregate with cancer nor polyposis in the large pedigree (Hansen 2015). BMPR1A Met460Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Met460Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the Protein kinase and IC domain (Howe 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Met460Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at