Jointly benchmarking small and structural variant calls with vcfdist

Recent improvements in long-read sequencing accuracy have enabled calling phased small and structural variants from a single analysis pipeline. Despite this, the current standard tools for variant calling evaluation are only designed for either small (vcfeval) or large (Truvari) variants. In this work we extend vcfdist — previously a small variant calling evaluator — to evaluate structural variants, making it the first benchmarking tool to jointly evaluate phased single-nucleotide polymorphisms (SNPs), small insertions/deletions (INDELs), and structural variants (SVs) for the whole genome. We find that a joint evaluation reduces measured false negative and false positive variant calls across the board: by 28.1% for SNPs, 19.1% for INDELs, and 52.4% for SVs over 50 bases. Building on vcfdist's alignment-based evaluation, we also jointly analyze phasing accuracy. vcfdist identifies that 43% to 92% of all flip errors called by standard phasing evaluation tool WhatsHap are false positives due to differences in variant representations.