several genes are reported in "PREDICTED_LOF" for a balanced translocation

[Nehir291]

bug report

I have a balanced translocation (CTX) case and it has several genes (475 genes) under PREDICTED_LOF. However, one CTX breakpoint hits an intron of a gene, whereas the other breakpoint is intergenic. How this CTX is calculated as PREDICTED_LOF?

Thanks.

[gokalpcelik]

Gene that CTX hits the intron must be broken in the midst of its coding frame (exon continuation is broken) therefore PREDICTED_LOF should be justified for that matter. If both breakpoints were in the intergenic region then PREDICTED_LOF assessment might have been problematic.

[Nehir291]

Thanks for the response and clarifying that. The breakpoints are not overlapping at any exon (one bp is intergenic, the other is in intronic site). I still don't see how so many genes have been computed under PREDCITED_LOF.

[epiercehoffman]

Hi @Nehir291, please refer to the SVAnnotate tool documentation for definitions of each annotation: https://gatk.broadinstitute.org/hc/en-us/articles/21905053774363-SVAnnotate. For translocations, PREDICTED_LOF is assigned if a breakpoint falls at any point in the transcript, so an intronic breakpoint would still be annotated as PREDICTED_LOF for any impacted genes. This is because only part of the gene exists on each chromosome after the translocation, which is likely to result in a truncated transcript subject to nonsense-mediated decay.

Perhaps in some cases this definition is overly permissive, such as if only the UTR or one shorter exon is removed by the translocation - those cases could be worth revisiting.

I hope this helps explain the behavior you are seeing. If this does not fully explain all the PREDICTED_LOF annotations you are observing, please share the CTX breakpoints, the annotations, the SVAnnotate version, and the GTF used so we can investigate further.