Although these relatively common (1 5% frequency) variants were computationally predicted to be functionally benign (22), our experimental data provide molecular evidence that they could have functional impact in cellular signaling regulation as well.
Greater sequencing depth will also increase sensitivity to detect smaller changes in relative expression, however this does not guarantee that these changes have functional impact in the biological system under study as opposed to tolerated fluctuations in transcript abundance [ 20].
The balance impairment may have functional impact and it might be addressed with proper clinical interventions.
A previous study reported that the RM11 yeast strain lacks the three last introns of COX1 ; recombination in these intronic regions is therefore unlikely to have a functional impact as they are not essential (Dimitrov et al. 2009).
However, a second hypothesis is that because conserved regions are indeed likely to have important functions, variants that persist within these regions are actually those that are less likely to have functional effects, as variants that impact function are likely to reduce fitness and be subjected to negative selection pressure.
We refer to these variants of low (≤ 1% MAF) or unknown frequency and having potentially functional impact as 'rare functional variants' (RFVs).
We also predict that the L861Q mutation in ErbB3 and ErbB4 may not have the same functional impact as in EGFR because ErbB3 and ErbB4 conserve a leucine at the Y764 position (Figure 4C).
Compared with the SMN1 gene, a single nucleotide substitution identified in SMN2 has a profound functional impact as only 10% of SMN2 translated products are full-length and stable (6).
The resulting interstitial deletion may have little functional impact on the protein, however, as exon 11 is very poorly conserved and exon 12 is very small.
Usage of alternative isoforms can have drastic functional impact, for instance by loss of functional protein domains.
However, a substantial proportion of differences may have no functional impact on human-specific diseases.
