We study low energy implications of F-theory GUT models based on SU(5) extended by a U(1)' symmetry which couples non-universally to the three families of quarks and leptons. This gauge group arises naturally from the maximal exceptional gauge symmetry of an elliptically fibred internal space, at a single point of enhancement, E_8supset SU(5)times SU(5)'supset SU(5)times U(1)^4. Rank-one fermion mass textures and a tree-level top quark coupling are guaranteed by imposing a Z_2 monodromy group which identifies two abelian factors of the above breaking sequence. The U(1)' factor of the gauge symmetry is an anomaly free linear combination of the three remaining abelian symmetries left over by Z_2. Several classes of models are obtained, distinguished with respect to the U(1)' charges of the representations, and possible extra zero modes coming in vector-like representations. The predictions of these models are investigated and are compared with the LHC results and other related experiments. Particular cases interpreting the B-meson anomalies observed in LHCb and BaBar experiments are also discussed.