Today's commercial transports are, in general, very safe. Other than deliberate human action (terrorism, suicide, sabotage) it usually takes a series of problems and an incorrect reaction from the pilot before the aircraft is lost. As a general rule, every system on the aircraft must demonstrate that it will not fail any more often than once in 10^-9 hours. So you will frequently have 2 or 3 redundant systems for every necessary function.
If you want a believable scenario, however, there are lots of plausible ones to choose from. Poor maintenance practices lead to an engine being taken off the wing for inspection (normal) but not properly reattached and it breaks loose during the flight. Here's an example of a real accident:
https://en.wikipedia.org/wiki/American_Airlines_Flight_191 in which everyone aboard died. You'll see from the description that there was the engine separation that ruptured hydraulic lines on that wing, that retracted the slats on that wing, changing the lift capability of the wing, which therefore raised the stall speed of the wing to a speed higher than what the airplane was currently doing, and the fact that the aircraft did not have a good stall warning system all lead to he crash. Removing any one of those factors would probably have allowed the pilots to recover and return to the airport.
Midair collisions do happen, infrequently, again only as a result of at least one error by pilots and/or ATC. Usually several. These are usually fatal to everyone involved, though in rare instances one of the aircraft have been able to land. Here's one:
https://en.wikipedia.org/wiki/Überlingen_mid-air_collision where both aircraft were lost and here's another:
https://en.wikipedia.org/wiki/Gol_Transportes_Aéreos_Flight_1907 where one plane survived.
A pilot not following procedure or not doing their checklists before takeoff can lead to a crash. One of those happened recently on a business jet. The pilots had quit doing the checklists and they forgot to disengage the gust lock before takeoff. The system should have prevented them from moving the throttles to takeoff power with the lock still engaged, which it failed to do, and the result was a crash that killed all 7 people on board.
http://www.ainonline.com/aviation-n...b-faults-pilot-compliance-gust-lock-giv-crash
If you have specific questions, feel free to PM me. I am a flight controls engineer, currently working for an avionics company but I have also worked for an aircraft manufacturer. I'm not a safety analysis expert but I know a fair amount about how commercial airplanes are designed.