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HaplotypeScore and nearby variants
I've run into a situation with HaplotypeScore that I just don't quite understand. This experiment consists of exome sequencing on 32 subjects with our phenotype of interest (no "normals"). A subset of the subjects have known variants that were identified by Sanger sequencing. One of those SNVs was called by UnifiedGenotyper, but then filtered out by VQSR. Here's the INFO for it:
As you can see, it's generally very good except that HaplotypeScore is high (the PASSing tranche in this dataset has a minimum VQSLOD of 3.17, so this is relatively close). When I started investigating in IGV, I noticed that a different subject carries a 3bp deletion 9 bases upstream (that is, nucleotides -11 through -9 relative to this SNV are deleted). My understanding of HaplotypeScore (which was confirmed by ebanks) is that it is calculated on each sample separately, and then averaged into a cohort score - so that deletion in a different sample shouldn't penalize my overall score.
But when I dropped the sample with the deletion and re-called everything, the HaplotypeScore dropped from 11.2 to 3.9. The other metrics didn't change substantially, and it now has a passing LOD. This says to me that the sample-level HaplotypeScore on that dropped sample was very high - but it doesn't look abnormal in IGV (the indel has no HS, of course).
Have I hit a dead end? I can't think of any other ways to look at this, and the answer may be that this is just an unlucky variant that can't be reliably classified (even with a process as cool as VQSR, there's bound to be a few of those). I'm about to re-call everything with HaplotypeCaller, do you have any other ideas of things I can try?