vcf2report - gbbarra

vcf2report turns a raw exome VCF + the patient's phenotype (HPO terms) into an auditable, clinical-grade ACMG variant report — locally, offline, in seconds. Exome interpretation today is slow and manual: an analyst hand-filters thousands of variants across several databases and matches each candidate to the patient's phenotype one by one. vcf2report runs the whole pipeline — parse ▸ QC ▸ annotate ▸ prioritize ▸ classify ▸ report — and returns a draft laudo for expert sign-off, showing the full ACMG reasoning for every variant: all 28 ACMG/AMP criteria, each with its concrete evidence value, its source (database + accession + date), and whether the deterministic engine decided it or it is honestly deferred to expert/model review. What makes it different from a black-box classifier: • Auditable — you see *why* a variant is Pathogenic; the trio/segregation criteria a single-proband VCF cannot support are marked N/A instead of guessed. • Brazilian population frequencies (ABraOM/SABE) on top of gnomAD, so a variant absent from gnomAD but common in Brazilians is correctly dropped. • ClinGen-calibrated AlphaMissense (PP3/BP4), deterministic PVS1 via the ClinGen SVI tree, and ontology-aware HPO phenotype matching (Lin/Information-Content). • Offline gnomAD: a 29.6M-variant DuckDB/Parquet store classifies a whole exome in ~7 s with the VCF never leaving the machine. Why it matters: validated against 200 real ClinVar variants (100 pathogenic / 100 benign, with ClinVar withheld from the engine), it produced 0 gross pathogenic↔benign flips and 100% precision when decisive. It is deliberately conservative — never dangerously wrong, and right whenever it commits — which is exactly the property a draft-generation aid for a clinician needs.

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