I'm trying to hunt for "rare mutations" which may serve as potential causation for some rare disease based on exome data. I just found two nonsynonymous mutations simply 3bp away from each other, which results in the alteration of two consecutive amino acids.
However the MAF (minor allele frequency) of both mutations are around 5%, look at below: http://genome.ucsc.edu/cgi-bin/hgTracks?position=chr3:56653424-56653427&hgsid=298081875&snp135Common=pack
Actually UCSC define them as "common SNP" (UCSC defines "rare mutation" as those with MAF <= 1% while when I analyzed I loosen the cutoff to 5% ), I'm just wondering are these two mutations in a haplotype? ie. are they always transmitted at the same time, or more like independently? If transmitted always together, the MAF of "combination of two mutations" will simply be ~5%, which kicks them out from candidates because 5% sounds NOT rare enough for rare disease; if independently, the possibly smallest MAF will simply be 5%*5%=0.25%, which makes them perfect candidate for rare disease.
Hope I've made it clear.