Does anyone know of any good algorithms for predicting the functional impact of indels? Similar in nature to SIFT, PolyPhen2, Panther, Mapp, etc. (however as far as I am aware, these are limited to nsSNPs).
Thank you for your input,
ANNOVAR, the Ensembl Variant Effect Predictor, and the SeattleSeq SNP Annotation site will each indicate whether an INDEL is intergenic, intronic, or exonic, and if exonic, whether or not it causes a frameshift. This is basically the extent of the functional prediction, as frameshift mutations are classically interpreted as loss-of-function. I should note, however, that I have been studying frameshifts in exome datasets and find that most (can't quantify) occur in the terminal exon. In other words, not all LOF frameshifts are created equal, so I would advise augmenting these calls with a sense of where the mutation occurred w.r.t. the transcript and protein domains.
I recall that all three support VCF, though I believe the Seattle requires a special format for INDELs. For what it's worth, I have found ANNOVAR to be accurate and intuitive to use, even for large datasets.
You need to examine the indel sequence both in isolation (the sequence itself) as well as within the context of the surrounding genomic sequence. An insertion could create a novel transcription factor (TF) binding motif, for example, and not analyzing the join between insertion and reference sequences will miss this. My approach is to analyze in parallel the alleles as though they are straight from a genome sequencing project. I'd ask questions like:
-Does the deletion alter an intron splice site or the prediction of such?
-Do the alleles alter predicted TF binding sites?
-Would the mRNA 3'-UTR structure or interaction with microRNAs be allele-specific?
-If the indel is not 140 bp in length, or some even multiple thereof, could it alter nucleosome phasing?
I like (and have voted up) what Aaron provides. I'm just expanding on that and emphasizing that you may need to think beyond available tools to a whole range of functional consequences.