VSQR filtered true rare variants
I use GATK to call variants and variant quality recalibration. What I have is usually several samples of different diseases and I am looking for the rare mutations that are responsible for each disease. To utilize VSQR, I also add additional samples so that there are more than 30 samples when doing the joint calling. These additional samples are in house sequenced exomes with population and sequencing platform matched to the diseased ones. I thought the strategy worked quite well until I found that a disease causing variant was failed to pass VSQR filter. The VCF line of the variant is shown below (position is masked):
chr19 XXXXXXXX . C T 3130.29 VQSRTrancheSNP99.00to99.90 AC=2;AF=0.016;AN=128;BaseQRankSum=-3.027;ClippingRankSum=-2.056;DP=3336;FS=7.171;InbreedingCoeff=0.9834;MLEAC=2;MLEAF=0.016;MQ=59.62;MQ0=0;MQRankSum=0.865;NEGATIVE_TRAIN_SITE;QD=32.61;ReadPosRankSum=1.928;VQSLOD=-3.835e+00;culprit=InbreedingCoeff GT:AD:GQ:PL 0/0:31,0:99:0,111,1083 0/0:7,0:39:0,39,445 0/0:28,0:83:0,83,755 0/0:56,0:99:0,168,1983 0/0:78,0:99:0,288,4190 0/0:90,0:99:0,271,3267 0/0:85,0:99:0,254,3098 0/0:93,0:99:0,280,3435 0/0:91,0:99:0,271,3237 0/0:100,0:99:0,301,3764 0/0:92,0:99:0,277,3387 0/0:73,0:99:0,218,2595 0/0:57,0:99:0,171,2166 0/0:91,0:99:0,274,3398 0/0:89,0:99:0,331,5082 0/0:75,0:99:0,226,2798 0/0:77,0:99:0,232,2887 0/0:76,0:99:0,227,2861 0/0:95,0:99:0,286,3578 0/0:73,0:99:0,218,2622 <strong>1/1:0,96:99:3192,289,0</strong> 0/0:60,0:99:0,181,2172 0/0:60,0:99:0,181,2258 0/0:84,0:99:0,251,3033 0/0:62,0:99:0,187,2253 0/0:69,0:99:0,208,2551 0/0:71,0:99:0,214,2628 0/0:95,0:99:0,286,3474 0/0:76,0:99:0,227,2738 0/0:83,0:99:0,250,3070 0/0:78,0:99:0,233,2868 0/0:20,0:57:0,57,504 0/0:33,0:99:0,99,844 0/0:45,0:99:0,137,1218 0/0:40,0:99:0,119,1044 0/0:31,0:93:0,93,855 0/0:20,0:60:0,60,563 0/0:27,0:81:0,81,801 0/0:14,0:42:0,42,392 0/0:40,0:99:0,120,1219 0/0:42,0:99:0,125,1221 0/0:30,0:89:0,89,855 0/0:46,1:99:0,134,1320 0/0:65,0:99:0,193,1878 0/0:42,0:99:0,126,1307 0/0:30,0:90:0,90,9060/0:23,0:69:0,69,729 0/0:31,0:92:0,92,910 0/0:23,0:69:0,69,721 0/0:12,0:36:0,36,343 0/0:9,0:27:0,27,300 ./. 0/0:27,0:81:0,81,8050/0:5,0:15:0,15,146 0/0:24,0:72:0,72,711 0/0:27,0:81:0,81,813 0/0:27,0:81:0,81,813 0/0:31,0:92:0,92,935 0/0:14,0:42:0,42,409 0/0:42,0:99:0,126,1258 0/0:13,0:39:0,39,401 0/0:53,0:99:0,159,1575 0/0:37,0:99:0,106,982 0/0:54,0:99:0,162,1604 0/0:58,0:99:0,174,1743<br />
As you can see, there's only one homozygous variant found on one patient and only reference allele for the other patients. As 'culprit=InbreedingCoeff' indicated, the variant was not pass the filter because of the coefficient solely. Quoting from @Geraldine_VdAuwera: "This is a measure of the level of inbreeding of a group of samples.", I assume the failure means VSQR thinks the variant is too rare to be true! Am I right about it? I don't really see any other problem with the variant, either read depth, base quality or mapping quality is OK.
Should I use the inbreedingCoeff for VSQR if variants are called from samples of numbers of different families with different diseases and the aim is to find the rare mutations?