P244: Clinical profiles of 134 patients with alpha-mannosidosis from the velmanase alfa clinical program and SPARKLE registry

rescued".Vice versa, if the spliced-out base number was not a multiple of 3, the splicing consequence was "not-inframe splicing" and the possible deleterious effect caused by the variant was supposed to be "not-rescued".We also analyzed all LoF variants (n=116,859) in the ClinVar dataset and chose a nonsense variant in APC (NM_000038.6:c.288T>A) as an example to validate the rescue effect with minigene assay.Results: In loss-of-function (LoF) variants, compared with the variants that were predicted to be not-rescued, those which were predicted to be rescued had higher population maximum allele frequency (p=0.043) and lower proportion of singleton (p<0.001),corresponding to reduced selection pressure.In ClinVar dataset, the nonsense variant in APC (NM_000038.6:c.288T>A) was previously reported to cause attenuated familial adenomatous polyposis (AFAP).Minigene assay for this variant showed the existence of in-frame (69bp) splicing products, where the original deleterious nonsense variant was spliced out as predicted.This may explain the "attenuated" disease phenotype.Conclusion: In summary, we found that the splice-out of putative null variants is possibly associated with reduced selection pressure and attenuated disease phenotype, providing new insights into the human genetic architecture and clinical variant interpretation.