Spontaneous (de novo) mutations play an important role in the disease etiology of a range of complex diseases. Identifying de novo mutations (DNMs) in sporadic cases provides an effective strategy to find genes or genomic regions implicated in the genetics of disease. High-throughput next-generation sequencing enables genome- or exome-wide detection of DNMs by sequencing parents-proband trios. It is challenging to sift true mutations through massive amount of noise due to sequencing error and alignment artifacts. One of the critical limitations of existing methods is that for all genomic regions the same pre-specified mutation rate is assumed, which has a significant impact on the DNM calling accuracy.