A prefix is a letter or a group of letters that ………. at the beginning of a word.
I agree with Ahmed_btm that (1) ("comes") is the correct answer here. A relative clause doesn't always modify the noun that comes immediately before it. In this case, the relative modifies the noun phrase "a group of letters," whose head -- "group" -- is singular. Hence the verb should agree with the singular subject.
While answer (2) ("come") is not ungrammatical, since it is possible for the relative clause to modify the plural noun "letters," it gives the wrong meaning. With "come," the sentence would refer to groups like "unprenonre-unretromiscontraultra," whereas we want it to individual prefixes, such as "pre."