10-86917243-T-C
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM2PP3_StrongBS2
The NM_004329.3(BMPR1A):c.785T>C(p.Val262Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,524 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V262I) has been classified as Uncertain significance.
Frequency
Consequence
NM_004329.3 missense
Scores
Clinical Significance
Conservation
Publications
- generalized juvenile polyposis/juvenile polyposis coliInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
- juvenile polyposis syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
- polyposis syndrome, hereditary mixed, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- hereditary mixed polyposis syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- congenital heart defects, multiple typesInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- pulmonary arterial hypertensionInheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00 AC: 0AN: 250642 AF XY: 0.00
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461524Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727034 show subpopulations
Age Distribution
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
The BMPR1A c.785T>C; p.Val262Ala variant (rs770830310), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 411617). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.9). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
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Hereditary cancer-predisposing syndrome Uncertain:2
The p.V262A variant (also known as c.785T>C), located in coding exon 7 of the BMPR1A gene, results from a T to C substitution at nucleotide position 785. The valine at codon 262 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
This missense variant replaces valine with alanine at codon 262 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
Juvenile polyposis syndrome Uncertain:2
This missense variant replaces valine with alanine at codon 262 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 262 of the BMPR1A protein (p.Val262Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 411617). Invitae Evidence 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 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at