Independent evaluation of the AlphaGenome Variant Impact (AVI) score: Step 1 pre-registration, frozen (feasibility count, design decision rule, development-material exclusions)
Abstract
Second version of the study record: the frozen Step 1 pre-registration, deposited before any ClinVar data row has been counted and before any score has been retrieved. It adds to version 1: - the result of the registered feasibility look (bins of upper bounds only; `results/feasibility_look.json`); - the clarifications DV-001 to DV-003; - the preparation code and its outputs: - development positions from saturation genome editing, TraitGym and ncVarDB; - the GREGoR submitter file; - the MANE Select transcript table; - the ClinVar replacement history; - the UCSC coordinate chain; - the evidence files per development source; - the freeze manifest `prereg/MANIFEST_step1.sha256` (SHA-256 c1895e15713c583a10cded43be4bfd1021b2c6f3a89d89b3e9580eba90220445). The archive contains the files of commit 4fe8442488944400700cbe47fb6ce3541f4136cd. The position file is deposited separately as a deterministic gzip, because it is too large for the repository. Every checksum is in `SHA256SUMS_freeze.txt`. Verify the deposit by its contents against the named commit and the manifest. Licences of third-party content: - **MaveDB files** (`mavedb_records.zip`): score sets from MaveDB (Rubin et al., Genome Biology 2025). They are redistributed under their own licences, CC0 or CC BY 4.0, as given per score set in each `scoreset.json`; the record's CC BY-SA 4.0 licence does not apply to them. The source publications are listed in `prereg/01b_development_sources.md`. - **TraitGym positions** (in `development_positions.tsv.gz`): TraitGym (Benegas, Eraslan and Song, bioRxiv 2025, doi:10.1101/2025.02.11.637758), Hugging Face dataset `songlab/TraitGym` at revision 1fde19555fe8c0a55b1382bdf4c6f7082209f566, MIT licence. - **ncVarDB positions** (in `development_positions.tsv.gz`): ncVarDB (Biggs et al., Database 2020), GitHub `Gardner-BinfLab/ncVarDB` at commit 42828402cd3fea565308faaefa187189faf2ec79. The repository has no licence file, so only variant positions (factual genomic coordinates) are redistributed, with attribution. - **Gene regions:** derived from the NCBI RefSeq annotation GCF_000001405.40-RS_2025_08. Only gene coordinates are redistributed, with attribution to NCBI RefSeq. The first version (10.5281/zenodo.23186667) registered the feasibility look.
