Rent from Borgo Ognissanti. The airport will cost you about $40-50 more in airport rental fees plus about $30 in taxi fare from the city center.
I find it weird that dropping off at Piazzale Roma should carry an extra $50 fee over Mestre. That is news to me. Please check the consolidator website www.autoeurope.com and compare both drop off locations with the various deals offered (Europcar and Hertz are generally cheaper, both are located at Borgo Ognissanti in Florence and Piazzale Roma in Venice).
If you really have to pay $50 extra for Piazzale Roma, then yes, drop it in Mestre. You have to pass by Mestre to reach Venice, and all rental offices are near the Mestre station. From there you need to catch the train to Venezia Santa Lucia station. Be aware that if you choose to take a taxi from Mestre to Piazzale Roma instead of the train, then your $50 will be mostly gone in taxi fare, therefore you might as well drive to Piazzale Roma yourself and pay the extra drop off charge (if it really applies).