ExAC PLI score calculation

Question

[jonessara770]

Hello all,

could you please simply explain for me how PLI score has been calculated? can we use it to filter the list of variants? How can we justify that BRCA1 has pLI = 0.00 ?

Please don't point me to ExAC paper, I read it and I am totally confused now! Thanks Sara

[WouterDeCoster]

And what about the supplementary of the paper (part 4.1)?

Also, from the FAQ:

What are the constraint metrics? For synonymous and missense, we created a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer variants than expected. Negative Z scores are given to genes that had a more variants than expected.

For LoF, we assume that there are three classes of genes with respect to tolerance to LoF variation: null (where LoF variation is completely tolerated), recessive (where heterozygous LoFs are tolerated), and haploinsufficient (where heterozygous LoFs are not tolerated). We used the observed and expected variants counts to determine the probability that a given gene is extremely intolerant of loss-of-function variation (falls into the third category). The closer pLI is to one, the more LoF intolerant the gene appears to be. We consider pLI >= 0.9 as an extremely LoF intolerant set of genes.

[Shicheng Guo]

I am wondering why the authors don't provide a formula?