# Given a VCF of a human genome, how do I assess the quality against known SNVs?

I'm looking for tools to check the quality of a VCF I have of a human genome. I would like to check the VCF against publicly known variants across other human genomes, e.g. how many SNPs are already in public databases, whether insertions/deletions are at known positions, insertion/deletion length distribution, other SNVs/SVs, etc.? I suspect that there are resources from previous projects to check for known SNPs and InDels by human subpopulations.

What resources exist for this, and how do I do it?

To achieve (at least some of) your goals, I would recommend the Variant Effect Predictor (VEP). It is a flexible tool that provides several types of annotations on an input .vcf file. I agree that ExAC is the de facto gold standard catalog for human genetic variation in coding regions. To see the frequency distribution of variants by global subpopulation make sure "ExAC allele frequencies" is checked in addition to the 1000 genomes.

Output in the web-browser:

If you download the annotated .vcf, frequencies will be in the INFO field:

##INFO=<ID=CSQ,Number=.,Type=String,Description="Consequence annotations from Ensembl VEP. Format: Allele|Consequence|IMPACT|SYMBOL|Gene|Feature_type|Feature|BIOTYPE|EXON|INTRON|HGVSc|HGVSp|cDNA_position|CDS_position|Protein_position|Amino_acids|Codons|Existing_variation|DISTANCE|STRAND|FLAGS|SYMBOL_SOURCE|HGNC_ID|TSL|SIFT|PolyPhen|AF|AFR_AF|AMR_AF|EAS_AF|EUR_AF|SAS_AF|AA_AF|EA_AF|ExAC_AF|ExAC_Adj_AF|ExAC_AFR_AF|ExAC_AMR_AF|ExAC_EAS_AF|ExAC_FIN_AF|ExAC_NFE_AF|ExAC_OTH_AF|ExAC_SAS_AF|CLIN_SIG|SOMATIC|PHENO|MOTIF_NAME|MOTIF_POS|HIGH_INF_POS|MOTIF_SCORE_CHANGE


The previously mentioned Annovar can also annotate with ExAC allele frequencies. Finally, should mention the newest whole-genome resource, gnomAD.

• Very good suggestion. My understanding is that ExAC holds approx. 123K exomes and gnomAD now has around 15K genomes May 22 '17 at 16:55
• These are all great answers, but as this seems to be the community favorite, I will mark is as "the answer". But future readers: please look at the others! May 28 '17 at 19:12

The greatest protein coding variant catalogue is definitely ExAC (>65k individuals). They also published a blogpost where they describe how to reproduce figures in the paper (it is a good start how to get familiar with the dataset).

For the whole-genome variants I would look at the data created by 1000 genomes project (the latest release has more than 3k individuals). The integrated variant call sets can be downloaded though the portal and catalogue of SVs can be found here.

In this paper (also 1000 genomes project) they speak about non-precise placement of SVs by SV callers. I would keep this in mind for the comparison of your genome to the known variants.

• Thanks for the help. I'm a bit confused by the hyperlink at guide which describes the perl script needed. Using this script, this will create a VCF from an aggregated ~2.5K individuals? May 21 '17 at 2:29
• The script is part of VCFtools, they link it to manual of the package instead of the source code, you are expected to install the package, not just to download the script. I also found thay have started a portal on the welpage so I edited the answer. May 21 '17 at 11:17

Your best bet is to use programs that provide you an complete annotation of variants present in your VCF. Two examples are snpEff and Annovar. These programs work on known variants deem different sources and provide you with information on each item in your file, that you can filter after to try to understand the effects of each variant.

• There is now access to gnomAD with ANNOVAR, which is pretty cool. May 22 '17 at 19:30