In partnership with EFSA, we conducted a comprehensive literature search focused on Open Reading Frames (ORFs) for GMO risk assessment. Analysing over 15,000 references, we narrowed down to 307 pertinent documents. This research explored criteria for ORF definition, prediction, and selection within GMO risk assessment. Our findings emphasize the challenges in current prediction tools and data consistency. We proposed a conceptual workflow, aiming to integrate and optimize available tools, ensuring a reliable GMO risk assessment framework.