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Discovering singletons with GenotypeGVCFs?


I have several samples that I ran HaplotypeCaller (in normal mode) with that I am looking to discover germline variants from. I read that GenotypeGVCFs isn't good with discovering singletons, and it is likely that there will be many singletons in the samples that I have. Does anyone have a solution to this? I was planning on running GenotypeGVCFs on each sample individually so as to prevent singletons from being lost.


  • bhanuGandhambhanuGandham Cambridge MAMember, Administrator, Broadie, Moderator admin
    edited October 2019


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    Post edited by bhanuGandham on
  • gauthiergauthier Member, Broadie, Dev ✭✭✭

    Where did you read that GenotypeGVCFs "isn't good with discovering singletons"? A computational experiment I did years ago shows that there is no loss of singleton sensitivity with increasing cohort size: https://drive.google.com/open?id=0BzI1CyccGsZiTFYzeXMzNUYxU2s

    Analysis should never be performed on ungenotyped GVCFs. They contain a lot of low quality variants that are likely false positives and get removed by GenotypeGVCFs, which requires enough evidence that there is less than a 1/1000 chance of a false positive, by default. (About one in every thousand bases in the human genome is variant, so we require more confidence than a 1/1000 chance of FP.) Running GenotypeGVCFs on a multi-sample GVCF will increase the discovery power if there are variants with AC > 1 and variants with AC = 1 should be unaffected.

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