NM_004329.3:c.374G>A

BMPR1A · NP_004320.2:p.(Cys125Tyr) · NM_004329.3

GRCh37: chr10:88659591 G>A · GRCh38: chr10:86899834 G>A

Gene: BMPR1A Transcript: NM_004329.3

Final call

VUS

PM2 supporting PP3 strong

Variant details

Gene

BMPR1A

Transcript

NM_004329.3

Protein

NP_004320.2:p.(Cys125Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: the variant is absent from gnomAD, with observed allele frequency 0.

PP3 strong: missense REVEL score 0.978 exceeds the >=0.932 strong threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one strong and one supporting pathogenic criterion do not meet a listed pathogenic or likely pathogenic combination, and no benign rule is satisfied; therefore 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 assessed	PS1 could not be assessed because its agent did not produce valid output.
PS2	Not assessed	Not assessed: no proband phenotype, family-history, or confirmed maternity-and-paternity testing results are available to establish a de novo variant.
PS3	Not assessed	Not assessed: no variant-specific validated assay result establishes a damaging effect for BMPR1A p.Cys125Tyr.	oncokb
PS4	Not assessed	Not assessed: no case-control counts, odds ratio, or confidence interval were available to test PS4's >5.0 and non-1.0 confidence-interval requirement.
PM1	Not assessed	PM1 could not be assessed because its agent did not produce valid output.
PM2	Met	Met at supporting strength: the variant is absent from gnomAD, with observed allele frequency 0 meeting the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no pathogenic same-gene partner, affected-proband recessive context, or parental testing demonstrates this variant is in trans.
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 assessed	PM5 could not be assessed because its agent did not produce valid output.
PM6	Not assessed	Not assessed: no parental genotypes or proband disease documentation are available to support an assumed de novo occurrence.
PP1	Not assessed	Not assessed: no affected relatives, pedigree, meioses, or genotype-phenotype observations are available to evaluate cosegregation.
PP2	Not assessed	PP2 could not be assessed because its agent did not produce valid output.
PP3	Met	Met, strong: missense REVEL score 0.978 exceeds the generic PP3 strong threshold of >=0.932.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history data were available to determine whether they are highly specific for one genetic disease.
PP5	Not assessed	Not assessed: ClinVar contained no exact-variant record, so no expert-panel pathogenic or likely pathogenic classification was available.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD, giving observed allele frequency 0 versus the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant has observed allele frequency 0 in gnomAD, below the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carries this variant in the genotype state required for BS2 evaluation.
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrates preserved BMPR1A protein function or splicing for p.Cys125Tyr.	oncokb
BS4	Not assessed	Not assessed: no affected relatives with genotype results are documented, so lack of segregation cannot be demonstrated.
BP1	Not assessed	BP1 could not be assessed because its agent did not produce valid output.
BP2	Not assessed	Not assessed: no pathogenic same-gene partner or phase result establishes either trans occurrence in a fully penetrant dominant disorder or cis occurrence.
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 0.978 is above the generic BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no case evidence documented an alternate molecular basis for disease alongside this variant.
BP6	Not assessed	Not assessed: ClinVar contained no exact-variant record, so no expert-panel benign or likely benign classification was available.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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