The BMPR1A NM_004329.3:c.374G>A (NP_004320.2:p.(Cys125Tyr)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
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 Generic ACMG/AMP 2015 with ClinGen SVI recommendations. 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 strength: the variant is absent from gnomAD, with observed allele frequency 0 meeting the PM2 threshold of <=0.0001.
Met, strong: missense REVEL score 0.978 exceeds the generic PP3 strong threshold of >=0.932.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 supporting plus PP3 strong do not satisfy any generic ACMG/AMP pathogenic, likely pathogenic, benign, or likely benign combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.978. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BMPR1A, a transmembrane receptor kinase, is frequently altered by mutation and deletion in various cancers, including colorectal and endometrial cance
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 19 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers BMPR1A, so generic ACMG/AMP rules govern; the available evidence contains no case-control data, phenotype-specificity data, alternate molecular diagnosis, or exact-variant ClinVar expert-panel classification relevant to these criteria.
The variant is missense, so the generic computational-evidence assessment uses exactly one path: REVEL.
REVEL 0.978 supports PP3 at strong strength and does not support BP4; SpliceAI and BayesDel are not double-counted or substituted into this missense assessment.
Population evidence supports PM2 at supporting strength because the variant is absent from the default all-comers gnomAD datasets and concordantly absent from the available non-cancer subsets.
The absence of the variant does not meet the benign frequency thresholds for BA1 or BS1, and no healthy-adult genotype observation is available to assess BS2.
No criteria match.
PM2 is met at supporting strength. NM_004329.3:c.374G>A is absent from gnomAD v2.1 and gnomAD v4.1, with observed allele frequency 0, meeting the generic PM2 supporting threshold of <= 0.0001. The variant is also absent from the available gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome subsets. No VCEP-specific population source or threshold governs this case, so the all-comers datasets remain the default and the non-cancer subsets provide concordant supplementary evidence.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense substitution, NP_004320.2:p.(Cys125Tyr), so PP3 is assessed through the missense REVEL path only. REVEL is 0.978, meeting the generic PP3 strong threshold of >= 0.932 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for this missense PP3 assessment, and BayesDel is not available for ACMG strength calibration.
Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (strong): >= 0.932 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BA1 is not met. NM_004329.3:c.374G>A is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, below the generic BA1 stand-alone threshold of >= 0.05. The variant is also absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records. This is a single-nucleotide substitution, so the ACMG/AMP indel-calling caveat does not apply.
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. NM_004329.3:c.374G>A is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed allele frequency of 0, which is below the generic BS1 threshold of >= 0.01 for an allele frequency greater than expected for the disorder. The variant is also absent from the available non-cancer subsets.
BS1: Allele frequency is greater than expected for disorder.
The variant is a missense substitution, so BP4 is assessed through the missense REVEL path only. REVEL is 0.978, which does not meet any generic BP4 threshold, including the supporting threshold of <= 0.29. The SpliceAI max delta of 0.001 is not considered because splice predictions cannot provide BP4 support for a missense variant, and BayesDel has no generic ACMG-strength calibration.
Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The available case evidence does not report a clinically characterized proband, family history, or testing results for both biological parents. Therefore, confirmed maternity and paternity, de novo status, and absence of family history cannot be established for PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No variant-specific, validated functional assay result was identified for BMPR1A NM_004329.3:c.374G>A (p.Cys125Tyr). OncoKB explicitly reports no variant-specific reviewed functional evidence. A PubMed abstract describing functional effects of a different homozygous BMPR1A missense variant was reviewed, but it does not identify c.374G>A and therefore cannot support PS3 for this variant. The available evidence does not establish a reproducible, robust assay showing a damaging effect for the tested variant.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Not assessed: no case-control study data were available for NM_004329.3:c.374G>A, including an odds ratio or relative risk and its confidence interval. Therefore, the required comparison cannot be performed: OR/RR > 5.0 and confidence interval not including 1.0.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed because the available evidence does not establish that this variant is being evaluated in a recessive BMPR1A disorder, does not identify a pathogenic variant in the same gene, and provides no parental or other phase testing demonstrating the variants are in trans. No affected-proband observation supports a recessive allelic configuration.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The available case evidence does not report a clinically characterized proband or parental testing results. A de novo occurrence cannot be assumed without evidence that the variant is absent in the parents, and the available information does not establish that basis for PM6.
Assumed de novo, but without confirmation of paternity and maternity.
The available case evidence provides no affected relatives, pedigree, meioses, or genotype-phenotype observations. Consequently, cosegregation with disease and any strength increase from multiple affected family members cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Not assessed: the available case evidence does not provide the patient's phenotype or family history. Consequently, it cannot be determined whether the phenotype is highly specific for a disease with a single genetic etiology.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Not assessed: the exact variant has no ClinVar record, and therefore no exact-variant ClinVar expert-panel classification of pathogenic or likely pathogenic was available. Ordinary, aggregate, or non-expert assertions cannot be used for PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS2 cannot be assessed from the available evidence. The case contains no documented observation of NM_004329.3:c.374G>A in a healthy adult as a homozygote, heterozygote, or hemizygote, and no evidence establishes the required early-age full-penetrance context for applying the criterion.
BS2: Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No variant-specific, validated functional assay result was identified for BMPR1A NM_004329.3:c.374G>A (p.Cys125Tyr) showing no damaging effect on protein function or splicing. OncoKB explicitly reports no variant-specific reviewed functional evidence. The available material therefore cannot establish a well-established benign functional result or support BS3 at any strength.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available case evidence does not identify affected family members who were tested and found not to carry the variant. Lack of segregation therefore cannot be established, and the phenocopy caveat cannot be evaluated.
Lack of segregation in affected members of a family.
BP2 cannot be assessed because no pathogenic variant in the same gene is identified, no cis or trans phase result is provided, and the available evidence does not document a fully penetrant dominant BMPR1A disorder context for applying the trans pathway.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Not assessed: no evidence was available that this variant was found in a case with an alternate molecular basis for disease. The available records do not document a qualifying alternate molecular diagnosis for the case.
Variant found in a case with an alternate molecular basis for disease.
Not assessed: the exact variant has no ClinVar record, and therefore no exact-variant ClinVar expert-panel classification of benign or likely benign was available. Ordinary, aggregate, or non-expert assertions cannot be used for BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004329.3:c.374G>A in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Cys125Tyr). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004329.3:c.374G>A in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Cys125Tyr). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004329.3:c.374G>A in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Cys125Tyr). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004329.3:c.374G>A in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Cys125Tyr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
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 |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
The variant is a missense substitution, NP_004320.2:p.(Cys125Tyr), so PP3 is assessed through the missense REVEL path only. REVEL is 0.978, meeting the generic PP3 strong threshold of >= 0.932 calibrated by ClinGen SVI (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for this missense PP3 assessment, and BayesDel is not available for ACMG strength calibration.
Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (strong): >= 0.932 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so BP4 is assessed through the missense REVEL path only. REVEL is 0.978, which does not meet any generic BP4 threshold, including the supporting threshold of <= 0.29. The SpliceAI max delta of 0.001 is not considered because splice predictions cannot provide BP4 support for a missense variant, and BayesDel has no generic ACMG-strength calibration.
Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004329.3:c.374G>A in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Cys125Tyr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.978. BayesDel score = 0.561738.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.978. BayesDel score = 0.561738.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BMPR1A, a transmembrane receptor kinase, is frequently altered by mutation and deletion in various cancers, including colorectal and endometrial cance
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.