Fig. 1.

Conceptual classification of hotspot methods reviewed. Clusters methods focus on aggregating mutations by local regions in residue coordinates while 3D Clusters approaches agglomerate mutations in 3D coordinates. Position methods consider the specific mutation position and, generally, its sequence context. Other methods are described as miscellaneous that include those approaches focusing on evolutionary conservation, functional impact of mutations, structural features, overall statistics of mutations, and other concepts impacting non-coding mutations such as chromatin domains.