NOP16 was the third most important mutation (6.84%) in a reduced-size cohort of 117 patients with Chronic Lymphocytic Leukemia (CLL) whose most recurrent mutations were NOTCH1 (9.4%) and SF3B1 (8.55%). In this paper we analyzed the effect of the NOP16 mutation in gene expression. The NOP16 mutation was predicted with 100% accuracy using a small-scale signature formed by the 26 genes with the highest Fisher's Ratio. SLC39A4 (ZIP4) and WARS are the most discriminatory genes of this mutation providing a predictive accuracy of 97.4%. The Fold Change analysis also confirmed a very important role of the light (IGKV3D-11, IGKC and IGLJ3) and heavy (IGHG1) chain immunoglobulins, SOX11, CCND1 and CHL1. This analysis also highlights the importance of several mechanisms such as the ZIP4-related apoptosis, the SOX11-CCND1 over expression relationship observed in mantle cell-lymphoma, and CHL1 down regulation and over expression of the midkine-neurite growth-promoting factor that enhances the angiogenic and proliferative activities of cancer cells in different types of solid cancers. Besides, the holdout stability analysis has shown the importance of Signaling Events of B Cell Receptor (BCR), P53 signaling, Infectious disease, and TGF-beta Receptor Signaling. The integration of the NOP16 mutation with the IgHV, NOTCH1 and SF3B1 mutations, that were previously analyzed, confirmed that these mutations only share two high discriminatory genes: IGHG1 and RGS13. These genes are involved in different mechanisms concerning signaling and the immunological system. This analysis opens novel working hypothesis for CLL treatment and prognosis.