high frequency protein truncating variants in hg19

Question

[giovanni.birolo]

Hello, in a whole-exome dataset of healthy individuals I am working with, I noticed some high frequency protein truncating variants. I find this strange and confusing, since I generally expect PTV to be deleterious and thus low frequency. For instance, rs72559129 is a frameshift variant with allelic frequency that is almost 1, both in my dataset and in gnomAD. How do I interpret this? Which allele is functional, the rare one, the common one, both? This is just one example but there are dozens. Is this due to a problem with the reference (hg19) or the transcript annotation? Am I missing something?

Any pointer is welcome.

Thanks

Answer 1

[WouterDeCoster]

Since I generally expect PTV to be deleterious and thus low frequency.

But that's not necessarily correct. Depending on the gene PTV mutations are tolerated. See also https://www.biorxiv.org/content/10.1101/531210v2