rs576247658
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 5P and 9B. PM1PP2PP3_ModerateBP6BS1BS2
The NM_004329.3(BMPR1A):āc.1235T>Cā(p.Val412Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V412G) has been classified as Uncertain significance.
Frequency
Consequence
NM_004329.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR1A | NM_004329.3 | c.1235T>C | p.Val412Ala | missense_variant | 11/13 | ENST00000372037.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR1A | ENST00000372037.8 | c.1235T>C | p.Val412Ala | missense_variant | 11/13 | 1 | NM_004329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251466Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135912
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727240
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74470
ClinVar
Submissions by phenotype
Juvenile polyposis syndrome Uncertain:1Benign:2Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 01-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces valine with alanine at codon 412 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast cancer (PMID: 25186627) and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 12/282860 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 2023 | This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 07, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 26, 2023 | This missense variant replaces valine with alanine at codon 412 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast cancer (PMID: 25186627) and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 12/282860 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 | Nov 03, 2022 | 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. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2017 | Variant summary: The c.1235T>C (p.Val412Ala) in BPMR1A gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the catalytic domain of the serine/threonine kinase, although the functional impact of this missense change is yet to be studied. The variant is present at a low frequency in large control population datasets of ExAC and gnomAD (0.000027; 3/121412 chrs tested and 0.00004; 12/277214 chrs tested, respectively) predominantly in individuals of African ancestry at frequencies that exceed the estimated maximal expected allele frequency of a pathogenic variant (0.000002). The variant has been reported in at least two affected individual (LS, BrC) via published reports and cited as VUS by a reputable database/diagnostic laboratory. In addition, the variant was identified in an unaffected individual undergoing genetic testing due to an extensive family history of BrC (three sisters and paternal aunt and 1st cousin). This individual also tested positive for a pathogenic mutation PMS2 c.2186_2187delTC p.L729fs*6 and likely pathogenic variant PALB2 c.801_802dupTA p.K268fs*12 (internal LCA data). Taken together, the variant was classified as Likely Benign until more data becomes available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast cancer, Lynch syndrome-related cancer(s) and/or polyps or other cancers (PMID: 25186627, 25980754, 36315513, 32459922); This variant is associated with the following publications: (PMID: 25980754, 25186627, 36315513, 32459922) - |
BMPR1A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2024 | The BMPR1A c.1235T>C variant is predicted to result in the amino acid substitution p.Val412Ala. This variant has been reported in individuals with a history of breast cancer and suspected Lynch syndrome (Tung et al. 2015. PubMed ID: 25186627; Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/216576/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 24, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at