> For the complete documentation index, see [llms.txt](https://help.connected.illumina.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://help.connected.illumina.com/annotation/core-functionality/consequence-prioritization.md). # Consequence Prioritization Depending on the representation of a genetic variant (e.g. right vs. left aligned) the effect on the transcript may differ, leading to a possibility of different set of consequence annotations for the same variant. Even though both representations of a genetic variant correspond to the exact same haplotype, one may be annotated as more pathogenic than the other. We hypothesize that reporting of variants as likely pathogenic when the same exact haplotype can be interperted in a less pathogenic way is less likely to reflect the realized functional impact. As such, we report the set of consequences with lowest priority. The priority of a set of consequences is determined by the highest priority consequence within that set. ## Conceptual Priority Tiers Variants are ranked using two principles, (1) variant pathogenicity (2) annotation definition. The annotations are first ranked based on pathogenicity, then the annotations are given a lower priority if their definition is loss of a specific sequence. Variants types that are defined as the loss of a specific sequence are ranked at the bottom of the list so that if there exists a representation of the variant that does not result in the loss of that specific sequence, that representation should be preferred. ### Prioritization Ordering (Very Low Probability of Harm) 1. synonymous\_variant 2. start\_retained\_variant 3. stop\_retained\_variant 4. transcript\_variant 5. non\_coding\_transcript\_variant 6. non\_coding\_transcript\_exon\_variant 7. mature\_miRNA\_variant 8. coding\_sequence\_variant 9. intron\_variant 10. upstream\_gene\_variant 11. downstream\_gene\_variant 12. exon\_variant (Low Probability of Harm) 13. splice\_region\_variant 14. splice\_donor\_region\_variant 15. splice\_donor\_5th\_base\_variant 16. splice\_polypyrimidine\_tract\_variant 17. exonic\_splice\_region\_variant 18. regulatory\_region\_variant 19. three\_prime\_UTR\_variant 20. five\_prime\_UTR\_variant 21. protein\_altering\_variant (High Probability of Harm) 22. missense\_variant 23. inframe\_indel 24. inframe\_insertion 25. stop\_gained 26. frameshift\_variant 27. inframe\_deletion 28. start\_lost 29. stop\_lost 30. splice\_donor\_variant 31. splice\_acceptor\_variant Consequences not in the above list are treated as lowest priority. ## Disabling Consequence Prioritization If the user is not interested in such consequence prioritization, they can disable it via the `--disable-consequence-prioritization` command line option. In this case, the consequence list for the left aligned variant will be reported. ## References * Ensembl Variant Effect Predictor consequence definitions and prioritization context: --- # Agent Instructions This documentation is published with GitBook. GitBook is the documentation platform designed so that both humans and AI agents can read, navigate, and reason over technical content effectively. Learn more at gitbook.com. ## Querying This Documentation If you need additional information that is not directly available in this page, you can query the documentation dynamically by asking a question. Perform an HTTP GET request on the current page URL with the `ask` query parameter, and the optional `goal` query parameter: ``` GET https://help.connected.illumina.com/annotation/core-functionality/consequence-prioritization.md?ask=&goal= ``` `ask` is the immediate question: it should be specific, self-contained, and written in natural language. `goal` is optional and describes the broader end goal you are ultimately trying to accomplish on behalf of the user. GitBook uses it to tailor the answer towards what is most useful for that goal. The response will contain a direct answer to the question and relevant excerpts and sources from the documentation. Use this mechanism when the answer is not explicitly present in the current page, you need clarification or additional context, or you want to retrieve related documentation sections.