The most likely response to have a harmful effect on an organism would be "a deletion of 3 bases near the center of a gene."
This is because a deletion can lead to a frameshift mutation if it does not occur in multiples of three, but even in the case of a three-base deletion, it may remove an entire amino acid from the protein, which can significantly alter the protein's structure and function.
In contrast, a substitution of a single base (thymine for adenine) may or may not have an effect depending on whether it changes the amino acid (which is determined by the redundancy in the genetic code) and its position in the protein.
So, while not all mutations are harmful, the deletion of three bases in the center of a gene poses a higher risk of disrupting the normal function of the encoded protein.