Splicing factor (trans-acting) mutations and their impact on splicing in hematologic malignancies. (A) SF3B1 mutations lead to alternative 3′ splicing site (SS) usage because of the increased recognition of cryptic splice sites between the branch point and the canonical 3′ splice site. (B) U2AF1 mutations affect 3′ splice site recognition, leading to an increase in exon skipping because of use of an alternative splice sites. S34F-mutant-U2AF1 losses affinity for the 3′ SS motif when a T(U) is present in position −3. Conversely, mutations at the Q157 residue promote the recognition of 3′ SS when a G is present in position +1 and repress those bearing an A. (C) SRSF2 mutations affect its normal RNA-binding activity to the consensus ESE motif (SSNG). Mutant SRSF2 recognizes with higher affinity the CCNG motif vs the GGNG, promoting or repressing the inclusion of exons containing C- or G-rich motifs. (D) ZRSR2 loss-of-function mutations specifically affect splicing of U12-type introns leading to intron retention. BP, branch point; Py-tract, polypyrimidine-tract; snRNP, small nuclear ribonucleoproteins; Y, pyrimidine.