Variant classification summary

NM_004329.3:c.1420G>C

BMPR1A · NP_004320.2:p.(Val474Leu) · NM_004329.3

GRCh37: chr10:88683210 G>C · GRCh38: chr10:86923453 G>C

Gene: BMPR1A Transcript: NM_004329.3

Final call

VUS

PM2 supporting

Variant details

Gene

BMPR1A

Transcript

NM_004329.3

Protein

NP_004320.2:p.(Val474Leu)

gnomAD AF

7.68163346218654e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 grpmax FAF is 0.00008424, below the generic supporting threshold of 0.0001.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting criterion alone satisfies none of the pathogenic, likely pathogenic, benign, or likely benign combinations, so the call 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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic BMPR1A variant causing p.Val474Leu was identified, while the exact variant has conflicting ClinVar submissions.	clinvar PMID:25980754
PS2	Not assessed	Not assessed: no documented proband phenotype, family history, or confirmed maternity and paternity testing establishes a de novo occurrence.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or reviewed functional evidence was identified for BMPR1A c.1420G>C (p.Val474Leu).	oncokb PMID:25980754 PMID:25741868
PS4	Not met	Not met: no exact-variant affected-versus-control counts, odds ratio, or 95% confidence interval were reported to satisfy OR >5.0 with CI excluding 1.0.	PMID:25980754 PMID:15604628
PM1	Not assessed	Not assessed: p.Val474Leu may lie in an annotated kinase domain, but a well-established critical domain without benign variation is not documented.	clinvar
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 0.00008424, below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: inheritance mode, a pathogenic second allele, affected-proband data, and parent or offspring phase testing are not documented.	PMID:15604628
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different pathogenic missense change at BMPR1A residue Val474 is documented in the available evidence.	clinvar PMID:25980754
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental testing is available for this variant.
PP1	Not assessed	Not assessed: no affected relatives, matching phenotypes, variant genotypes, or informative meioses are documented.
PP2	Not assessed	Not assessed: BMPR1A loss-of-function disease evidence is available, but no benign-missense rate and common-missense-mechanism evidence are documented.	pvs1_gene_context
PP3	Not met	Not met: missense REVEL score 0.454 is below the generic PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not provided, so specificity for a single BMPR1A-related disease etiology cannot be judged.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and no exact-variant Pathogenic or Likely pathogenic expert-panel classification.	clinvar PMID:25980754
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00008424, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00008424, below the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes but no documented healthy adult carrier with age and phenotype information.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated assay showing preserved BMPR1A protein function or splicing was identified for c.1420G>C (p.Val474Leu).	oncokb PMID:25980754 PMID:25741868
BS4	Not assessed	Not assessed: no tested affected relatives lacking the variant are documented, and phenocopy or multiple-variant explanations cannot be evaluated.
BP1	Not assessed	Not assessed: BMPR1A loss-of-function evidence exists, but the evidence does not show that disease is caused primarily by truncating variants.	pvs1_gene_context
BP2	Not assessed	Not assessed: no individual-level co-occurrence with a pathogenic variant or phase result establishes cis or trans for this variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.454 exceeds the generic BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis or second causal variant is documented for this patient.
BP6	Not met	Not met: the benign and likely benign ClinVar assertions are single-laboratory submissions, with zero exact-variant expert-panel submissions.	clinvar PMID:25980754
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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