No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.BMPR1A is a cell-surface receptor that helps transmit bone morphogenetic protein signals, regulating cell growth, specialization, death, bone formation, and fat-cell development. Inherited BMPR1A defects are associated with juvenile polyposis syndrome and Cowden syndrome, which can cause gastrointestinal polyps. BMPR1A acts as a tumor suppressor, and inherited defects increase the risk of gastrointestinal and colorectal cancer.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting: gnomAD v4.1 total AF is 2.91252e-05, below the generic PM2 threshold of 0.0001.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (supporting) is the only applied criterion and does not satisfy any generic ACMG/AMP pathogenic, likely pathogenic, benign, or likely benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 47 / 1,613,722 alleles. Recorded AF 2.91252e-05. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 1.06096e-05; MAF= 0.00106%, 3/282764 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138543; MAF= 0.01385%, 1/7218 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Likely benign · 1 Likely Benign · 1 Benign.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant has previously been reported in somatic cancers (COSMIC; COSV63135122, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 4 not met · 12 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No applicable BMPR1A-specific VCEP or ClinGen specification was available, so generic ACMG/AMP criterion concepts were used where applicable.
The exact variant is synonymous, and the available evidence contains no case-control enrichment statistic, patient-level phenotype, alternative molecular diagnosis, or qualifying expert-panel ClinVar assertion for this criterion group.
Population evidence supports PM2 at supporting strength because the variant remains below AF 0.0001 in gnomAD v2.1, gnomAD v4.1, and the provided non-cancer subsets.
BA1 and BS1 are not met because all provided allele frequencies are far below their generic thresholds of 0.05 and 0.01, respectively.
BS2 is not assessed because one gnomAD v4.1 homozygote does not establish observation in a healthy adult with known phenotype and penetrance.
No criteria match.
No applicable BMPR1A-specific VCEP or CSPEC was identified, so the supplied generic PM2 threshold was used. The variant is rare in population databases: gnomAD v4.1 all-comers total AF is 2.91252e-05 (47/1613722 alleles), gnomAD v2.1 total AF is 1.06096e-05 (3/282764 alleles), and the provided non-cancer subsets are also below 0.0001. These data meet the generic PM2 supporting threshold of <=0.0001.
Generic PM2: allele frequency <=0.0001, applied at supporting strength; no applicable gene-specific specification was available.
PP5 is not met because ClinVar variation 460476 has zero expert-panel submissions. Its exact-variant assertions are from individual clinical laboratories and are Likely benign or Benign; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify for PP5.
Apply PP5 only when an exact-variant ClinVar expert-panel classification is Pathogenic or Likely pathogenic; laboratory submissions, aggregate ClinVar labels, and non-expert assertions are excluded.
No applicable BMPR1A-specific VCEP or CSPEC was identified, so the generic ACMG/AMP population threshold was used. BA1 requires allele frequency >=0.05. The highest provided frequency is below this threshold: 0.00049456 (0.04946%) in the gnomAD v3.1 non-cancer remaining-individuals subgroup; gnomAD v4.1 all-comers has total AF 2.91252e-05, one homozygote, and highest reported population AF 0.000390625. Therefore BA1 is not met.
Generic ACMG/AMP BA1: allele frequency >=0.05; no applicable gene-specific specification was available.
No applicable BMPR1A-specific VCEP or CSPEC was identified, so the supplied generic BS1 threshold was used. BS1 requires allele frequency >=0.01. The highest provided frequency is 0.00049456 (0.04946%) in the gnomAD v3.1 non-cancer remaining-individuals subgroup, while gnomAD v4.1 all-comers has total AF 2.91252e-05 and highest listed subgroup AF 0.000390625. These frequencies are below 0.01, so BS1 is not met.
Generic BS1: allele frequency >=0.01; no applicable gene-specific specification was available.
BP6 is not met because ClinVar variation 460476 has zero expert-panel submissions. Although the exact variant has individual laboratory Likely benign and Benign assertions, those ordinary submissions and the aggregate ClinVar label are explicitly excluded from BP6.
Apply BP6 only when an exact-variant ClinVar expert-panel classification is Benign or Likely benign; ordinary laboratory submissions, aggregate labels, and non-expert assertions are excluded.
No case-specific evidence documents that NM_004329.3:c.117C>T arose de novo in an affected proband. The available records do not provide parental genotypes, confirmed maternity and paternity, parental testing methods, or phenotype information sufficient to evaluate a de novo event.
No validated, variant-specific functional assay was identified for NM_004329.3:c.117C>T (NP_004320.2:p.(Ser39=)). The available literature and case evidence contain no assay result demonstrating abnormal BMPR1A function, and general ACMG/AMP guidance cannot substitute for direct functional evidence; therefore PS3 is not assessed.
No case-control cohort, affected-versus-control enrichment analysis, odds ratio, likelihood ratio, or statistically supported prevalence comparison for the exact BMPR1A NM_004329.3:c.117C>T variant was identified. The available records do not provide the quantitative or cohort-level evidence required to assess PS4.
PS4 requires statistically significant enrichment of the exact variant in affected individuals compared with an appropriate control population; no applicable quantitative threshold or qualifying dataset is available.
No case-specific evidence documents a suspected de novo occurrence of NM_004329.3:c.117C>T without parental testing. The available records do not provide a proband report, phenotype assessment, parentage information, or meiosis-related evidence supporting PM6.
No case-specific family segregation data are available for NM_004329.3:c.117C>T. The records do not identify affected or unaffected relatives carrying or lacking the variant, the number of informative meioses, or phenotype concordance across relatives.
The case materials do not provide a documented patient phenotype, a highly specific syndrome presentation, or a phenotype-specific differential for the exact BMPR1A NM_004329.3:c.117C>T variant. General BMPR1A/JPS gene-disease information without patient-level phenotype evidence is insufficient for PP4.
PP4 requires a patient's phenotype or family history to be highly specific for a disease associated with the gene; gene-level disease association alone is insufficient.
BS2 requires observation of the variant in healthy adults, including a homozygous observation for a dominant disorder. gnomAD v4.1 reports one homozygote, but the available population record does not establish that the individual was a healthy adult or provide phenotype and penetrance information; the non-cancer subsets report zero homozygotes. The homozygote count alone is therefore insufficient to apply BS2.
Generic ACMG/AMP BS2: observation in healthy adults, including homozygous observation for a dominant disorder; phenotype and unaffected status must be established.
No validated, variant-specific functional assay was identified for NM_004329.3:c.117C>T (NP_004320.2:p.(Ser39=)). The available literature and case evidence contain no assay result demonstrating preserved BMPR1A function with appropriate controls, and general ACMG/AMP guidance cannot substitute for direct functional evidence; therefore BS3 is not assessed.
No case-specific non-segregation evidence is available for NM_004329.3:c.117C>T. The records do not identify clinically unaffected relatives who were tested and found to carry the variant, nor do they provide phenotype ascertainment or family structure needed to interpret such findings.
No applicable BMPR1A-specific VCEP specification was available, so the generic ACMG/AMP BP2 definition was used. BP2 requires documented allelic phase showing the assessed variant in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder. The available case evidence contains no affected-proband genotype, second pathogenic allele, or cis/trans phase determination for NM_004329.3:c.117C>T; therefore BP2 cannot be assessed.
Generic ACMG/AMP BP2: the assessed variant is observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder.
No qualifying evidence was identified that the exact BMPR1A NM_004329.3:c.117C>T variant explains a different molecular diagnosis in the patient or that an alternative pathogenic variant accounts for the phenotype. The available ClinVar benign assertions do not establish BP5, and no BP5-specific numeric likelihood-ratio threshold is provided by an applicable framework.
BP5 requires a pathogenic variant in another gene that explains the phenotype, or equivalent evidence for an alternative molecular diagnosis; no qualifying evidence is available.
BP7 is applicable in principle because NM_004329.3:c.117C>T is a synonymous substitution producing NP_004320.2:p.(Ser39=). The available SpliceAI result predicts no significant splice impact with a max delta score of 0.00, below the published <=0.1 low-impact reference threshold from Jaganathan et al. 2019 (PMID:30661751). However, BP7 also requires evidence that the affected nucleotide is not highly conserved, and no conservation assessment is available in the case evidence; the criterion therefore remains not assessed rather than met.
generic_acmg_bp7: synonymous_variant_requires_no_predicted_splice_impact_and_not_highly_conserved_nucleotide
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
No applicable BMPR1A-specific VCEP specification was available, so generic ACMG/AMP criteria were used. PM3 is intended for recessive disease and requires an affected individual with the assessed variant in trans with a pathogenic variant or other qualifying biallelic evidence. The governing disease context identifies BMPR1A-associated juvenile polyposis syndrome as autosomal dominant, and no recessive BMPR1A disease context or biallelic allelic model was established for this assessment; therefore PM3 is not applicable.
Generic ACMG/AMP PM3: evidence of the assessed variant in trans with a pathogenic variant in an affected individual for a recessive disorder; not applicable here because the established BMPR1A disease context is autosomal dominant.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
PP3 applies here only to a missense variant or to a splice-region/intronic variant assessed through the SpliceAI path. NM_004329.3:c.117C>T is a synonymous coding substitution producing NP_004320.2:p.(Ser39=), and no splice-region or intronic classification is present; therefore PP3 is outside scope and SpliceAI is not evaluated for this criterion.
scope_prefilter: requires_missense_or_splice_region_intronic_variant
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_repeat_region_indel
BP4 applies here only to a missense variant or to a splice-region/intronic variant assessed through the SpliceAI path. NM_004329.3:c.117C>T is a synonymous coding substitution producing NP_004320.2:p.(Ser39=), and no splice-region or intronic classification is present; therefore BP4 is outside scope and SpliceAI is not evaluated for this criterion.
scope_prefilter: requires_missense_or_splice_region_intronic_variant
Every interpreted variant in BMPR1A, mapped onto the exon structure of NM_004329.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern1 / 5,902 | 0.00017 |
| Remaining individuals6 / 62,448 | 9.6e-05 |
| South Asian4 / 91,066 | 4.4e-051 hom |
| European (non-Finnish)33 / 1,180,004 | 2.8e-05 |
| African/African American2 / 74,894 | 2.7e-05 |
| East Asian1 / 44,878 | 2.2e-05 |
| Remaining individuals1 / 7,218 | 0.00014 |
| East Asian1 / 19,948 | 5e-05 |
| European (non-Finnish)1 / 129,090 | 7.7e-06 |
This variant is present in gnomAD v4.1 (AF= 2.91252e-05; MAF= 0.00291%, 47/1613722 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.000169434; MAF= 0.01694%, 1/5902 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.
This variant is present in gnomAD v2.1 (AF= 1.06096e-05; MAF= 0.00106%, 3/282764 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138543; MAF= 0.01385%, 1/7218 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
BP7 is applicable in principle because NM_004329.3:c.117C>T is a synonymous substitution producing NP_004320.2:p.(Ser39=). The available SpliceAI result predicts no significant splice impact with a max delta score of 0.00, below the published <=0.1 low-impact reference threshold from Jaganathan et al. 2019 (PMID:30661751). However, BP7 also requires evidence that the affected nucleotide is not highly conserved, and no conservation assessment is available in the case evidence; the criterion therefore remains not assessed rather than met.
generic_acmg_bp7: synonymous_variant_requires_no_predicted_splice_impact_and_not_highly_conserved_nucleotide
PP3 applies here only to a missense variant or to a splice-region/intronic variant assessed through the SpliceAI path. NM_004329.3:c.117C>T is a synonymous coding substitution producing NP_004320.2:p.(Ser39=), and no splice-region or intronic classification is present; therefore PP3 is outside scope and SpliceAI is not evaluated for this criterion.
scope_prefilter: requires_missense_or_splice_region_intronic_variant
BP4 applies here only to a missense variant or to a splice-region/intronic variant assessed through the SpliceAI path. NM_004329.3:c.117C>T is a synonymous coding substitution producing NP_004320.2:p.(Ser39=), and no splice-region or intronic classification is present; therefore BP4 is outside scope and SpliceAI is not evaluated for this criterion.
scope_prefilter: requires_missense_or_splice_region_intronic_variant
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
7 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Location Proposed Criteria for Interpretation of Sequence Variants
Context ACMG/AMP/CAP workgroup development of general variant-classification standards based on literature review, laboratory surveys, expert opinion, and community input.
JPS 2.0 2.0 174900 BMPR1A SMAD4c AD All P and LP
Table 1, ACMG SF v3.1 gene and associated phenotypes recommended for return as secondary findings
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 2.91252e-05; MAF= 0.00291%, 47/1613722 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.000169434; MAF= 0.01694%, 1/5902 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.
This variant is present in gnomAD v2.1 (AF= 1.06096e-05; MAF= 0.00106%, 3/282764 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138543; MAF= 0.01385%, 1/7218 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 460476)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63135122, n = 1 times).
This variant does not lie in a statistically significant hotspot.