Variant classification summary

NM_004329.3:c.117C>T

BMPR1A · NP_004320.2:p.(Ser39=) · NM_004329.3

GRCh37: chr10:88649868 C>T · GRCh38: chr10:86890111 C>T

Gene: BMPR1A Transcript: NM_004329.3

Final call

VUS

PM2 supporting

Variant details

Gene

BMPR1A

Transcript

NM_004329.3

Protein

NP_004320.2:p.(Ser39=)

gnomAD AF

2.9125214875920388e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 total allele frequency is 2.91252e-05, below the generic PM2 threshold of 0.0001.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any pathogenic, likely pathogenic, benign, or likely benign combination threshold, so the result is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	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.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). 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. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_004329.3:c.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband parental-testing results, confirmed parentage, or phenotype data establish a de novo origin.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay result was identified for BMPR1A c.117C>T (p.Ser39=).
PS4	Not assessed	Not assessed: no case-control cohort, enrichment statistic, odds ratio, or likelihood ratio is available for the exact variant.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_004329.3:c.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 2.91252e-05, below the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: BMPR1A juvenile polyposis syndrome is autosomal dominant, so recessive biallelic PM3 evidence does not apply.	PMID:35802134
PM4	N/A	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.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). 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. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_004329.3:c.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no suspected de novo proband report or meiosis and parentage evidence is available without parental testing.
PP1	Not assessed	Not assessed: no affected-relative genotypes, informative meioses, or phenotype-concordant segregation data are reported.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_004329.3:c.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.117C>T is a synonymous coding substitution, not a missense or splice-region/intronic variant within PP3 scope.	generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient-level phenotype or highly specific BMPR1A-associated syndrome presentation is documented for the exact variant.
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions for the exact variant, and available laboratory assertions are benign rather than expert-panel pathogenic.	clinvar
BA1	Not met	Not met: the highest provided allele frequency is 0.00049456, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest provided allele frequency is 0.00049456, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD v4.1 shows one homozygote, but healthy-adult status and phenotype are not established.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no validated variant-specific assay demonstrated preserved BMPR1A function for c.117C>T (p.Ser39=).
BS4	Not assessed	Not assessed: no tested clinically unaffected relatives carrying the variant or phenotype-ascertained non-segregation data are reported.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_004329.3:c.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic allele or documented cis/trans phase is available for NM_004329.3:c.117C>T.
BP3	N/A	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.117C>T in BMPR1A is a synonymous (silent) substitution predicted to produce NP_004320.2:p.(Ser39=). 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. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.117C>T is a synonymous coding substitution, not a missense or splice-region/intronic variant within BP4 scope.	generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no evidence shows an alternative pathogenic variant or different molecular diagnosis explains the patient's phenotype.
BP6	Not met	Not met: ClinVar has zero expert-panel submissions, so the exact variant's laboratory Benign or Likely benign assertions cannot trigger BP6.	clinvar
BP7	Not assessed	Not assessed: synonymous c.117C>T has SpliceAI max delta 0.00, but the required nucleotide-conservation assessment is unavailable.	spliceai PMID:25741868

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