Thank you very much for the invaluable contribution you make with gnomAD. Your work is tremendously beneficial for those of us involved in diagnostics.
I would like to inquire about the 6-98835104-C-CG variant identified in the V4 dataset. I am keen to understand whether this variant is more likely a false negative or a genuine variant.
There is evidence suggesting that POU3F2 Loss of Function (LoF) variants are linked to a specific type of intellectual disorder. This particular variant is observed in 321 heterozygous cases, as it is predicted to result in a truncation of the protein. However, the frequency of this variant does not seem consistent with the prevalence of the associated disorder. Additionally, another variant at the same position (6-98835104-CG-C) is present in 28 heterozygous cases. The available reads in gnomAD suggest that this variant appears genuine, despite the challenging region for sequencing. Notably, both of these variants are absent in the V2 and V3 datasets.
In contrast, the next most frequent LoF variant in this gene, 6-98836151-C-CG, is found in 8 heterozygous cases and present in 1 heterozygous case in the gnomAD V3 dataset.
We recently encountered a case where a duplication was identified in a patient and subsequently confirmed by Sanger sequencing. Furthermore, these variants have not been commonly observed as false positives in our Whole Genome Sequencing cohort. Thus, I am left to wonder if they could potentially be false positives.
Thanks again for your help.