The effect of the SP variants on the biological processing of FIX. The pathogenic variants in FIX’s SP caused HB by missense variants and/or by aberrant pre-mRNA splicing. In nucleus, the gene was transcribed into pre-mRNA, and then the pre-mRNA was processed into mature mRNA. Some variants may disturb the processing of pre-RNA and lead to aberrant mature mRNA, which may generate aberrant protein products. The variants that did not disturb the process of splicing would cause missense variants. Missense variants in the SP h-region affected the cotranslational translocation function of the SP and produced the cytosol-located FIX, which was degraded by proteasome pathway. Those in c-region may disturb the cotranslational translocation and/or the SP cleavage. Additionally, a variation may cause HB by a mixture of above mechanisms. TSS, transcriptional start site; SRP, signal recognition particle.