Translational products encoded by novel ORFs may form protein-like structures and have biological functions

Translation products encoded by non canonical or novel open reading frame (ORF) genomic regions are generally considered too small to play any significant biological role, and dismissed as inconsequential. In this study, we show that mutations mapping to novel ORFs have significantly higher pathogenicity scores than mutations in protein-coding regions. Importantly, novel ORFs can translate into protein-like structures with putative independent biological functions that can be of relevance in disease states, including cancer. We thus provide strong evidence to support the systematic study of novel ORFs to gain new insights into normal biological and disease processes. One Sentence Summary Non coding regions may encode protein-like products that are important to understand diseases.