Variant classification summary

NM_000130.5:c.1601G>A

F5 · NP_000121.2:p.(Arg534Gln) · NM_000130.5

GRCh37: chr1:169519049 T>T · GRCh38: chr1:169549811 C>T

Gene: F5 Transcript: NM_000130.5

Final call

Benign

PS3 supporting BA1 stand-alone benign BS1 strong

Variant details

Gene

F5

Transcript

NM_000130.5

Protein

NP_000121.2:p.(Arg534Gln)

gnomAD AF

0.021432388235308703 (v4.1)

ClinVar

drug response

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: Factor V Leiden shows approximately tenfold slower activated-protein-C inactivation and increased thrombin generation.

2

BA1 stand-alone benign: Amish gnomAD v4.1 allele frequency is 9.32018%, above 5%.

3

BS1 strong: total gnomAD v4.1 allele frequency is 2.14324%, above 1% across several populations.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone supports Benign; BS1 is additionally strong, while PS3 supporting does not meet a pathogenic combination rule.

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	Not assessed: no verified previously pathogenic alternate-nucleotide change producing the same p.Arg534Gln substitution was identified.	clinvar PMID:21116184 PMID:12070000
PS2	Not assessed	Not assessed: no proband-level parental testing, confirmed maternity and paternity, de novo status, or family-history data are documented.
PS3	Met	Met at supporting: the Factor V Leiden allele slows activated-protein-C inactivation approximately tenfold and produces increased thrombin generation, but primary assay controls are not fully available.	PMID:21116184
PS4	Not assessed	Not assessed: no affected-case frequency or exact-variant case-control counts are available to calculate an OR and 95% CI against the PS4 >5.0 threshold.	gnomad_v4 PMID:23382263 PMID:12070000 PMID:19652888 PMID:21150787
PM1	Not met	Not met: hotspot testing was negative and no validated critical-domain evidence without benign variation places F5 residue 534 in PM1 territory.
PM2	Not met	Not met: gnomAD v4.1 shows AF 2.14324% with 450 homozygotes, far above the generic PM2 threshold of 0.01%.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband with a pathogenic allele in trans and no parental or offspring testing establishes phase for c.1601G>A.
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	Not assessed: no verified pathogenic different-missense comparator at F5 residue 534 was identified, and the candidate collection contains zero candidates.	pm5_candidates PMID:21116184 PMID:12070000
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental testing is available for NM_000130.5:c.1601G>A.
PP1	Not assessed	Not assessed: no multiple affected relatives, genotype results, phenotype concordance, or informative meioses are documented for co-segregation.
PP2	Not assessed	Not assessed: the case lacks gene-level evidence for both low benign missense variation and a common missense disease mechanism in F5.	gnomad_v4
PP3	Not met	Not met: the missense variant requires REVEL >= 0.644 for supporting PP3, but no REVEL score is available.
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: the exact-variant expert-panel ClinVar record is drug response, not Pathogenic or Likely pathogenic, so PP5 does not apply.	clinvar
BA1	Met	Met, stand-alone: the Amish gnomAD v4.1 AF is 9.32018%, exceeding the generic BA1 threshold of 5%.	gnomad_v4 gnomad_v2
BS1	Met	Met, strong: gnomAD v4.1 total AF is 2.14324%, exceeding the generic BS1 threshold of 1% and occurring across several populations.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 450 homozygotes, but healthy adult status and full early-age penetrance are not established.	gnomad_v4
BS3	Not met	Not met: functional evidence shows approximately 10-fold slower activated-protein-C inactivation and increased thrombin generation, not preserved Factor V function.	PMID:21116184
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are reported, so lack of segregation cannot be established.
BP1	Not assessed	Not assessed: loss-of-function support exists, but no variant-spectrum evidence shows that F5 disease is primarily caused by truncating variants.	pvs1_gene_context
BP2	Not assessed	Not assessed: no pathogenic variant in trans or cis with c.1601G>A is documented, and no phase information is available.
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: the missense variant requires REVEL <= 0.29 for supporting BP4, but no REVEL score is available.
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis is documented for a carrier of this exact variant.
BP6	Not met	Not met: the only exact-variant Benign ClinVar assertion is non-expert and flagged, with no expert-panel Benign or Likely benign classification.	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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