I use a 3-4 because I can stop the run easily but I have problems stopping the pass so I have an extra LB for coverage. I used to use a 3-3-5 for that reason, but recently switched to 3-4.
While it depends what team I'm playing, usually I'm in a 2-4-5 Nickel. I have 3-4 and 4-4 formations in my custom playbook as well. The playbook is called 'Nickel Multiple'.
I used to use 4-2-5 and dabbled in the 3-4, but they required to much micromanaging to be effective. The 425 gets great pressure, but sometimes has major alignment issues where the SS is assigned to man coverage on the opposite side of field as his assignment etc.
The 4-3 is what the developers wrote the code for, what is the most ironed out defense and allows for the most flexibility against the run and the pass. If you call the hotroutes for the defense you can get the same type of blitzes as seen in the other two defenses, the main difference being that you don't HAVE to do this to have a solid defense capable of stopping any sort of offense.
tl;dr: 4-3 is the best and most balanced defense in how this game was coded
