In silico analysis of missense Single Nucleotide Variants (SNVs) in HBB gene associated with the β-thalassemia

Abstract Background β-Thalassemia is a rapidly prevailing autosomal recessive disorder throughout the world. The human beta-globin gene (HBB) is responsible for the synthesis of the β-globin chains of hemoglobin, and numerous mutations in this gene, are correlated with the β-thalassemia. Among these mutations, Single Nucleotide Variations (SNVs) are the primary genetic factors behind the etiology of β-thalassemia. Objective This study aims to identify the pathogenic missense mutations from the conserved regions of β-globin, decreasing protein stability and altering molecular interactions and three-dimensional folding of the mutated proteins. The nominated mutations would, therefore, more likely to associate with the incidence of this disease. Methods Computational tools based on sequence homology (SIFT, PROVEAN, PANTHER & Mutation Assessor), supervised learning (SNAP2, PhD-SNP, SNP&GO, SuSpect & MutPred), and consensus-based algorithms (PredictSNP & PON-P2) pinpoints the potentially pathogenic missense variants from the HBB gene. Furthermore, the ConSurf tool screens mutations, specifically from the evolutionarily conserved regions of the protein. Finally, the mutations decreasing protein stability were compared with the native proteins' model to highlight the differences in 3D structure, molecular interactions, and protein folding. Results A total of 12 pathogenic missense mutations including, G25V, G25D, G25R, G65D, T39P, P37H, P37T, H93P, H93D, L97P, D100V, and P101R, are recognized from the beta-globin protein. These mutations were disturbing the molecular interactions of mutated proteins, decreasing the stability of this protein. Conclusions The identified mutations could be the potential genetic aberrations responsible for the beta-thalassemia, all these mutations, however, need experimental validations before their use for the screening and management of the β-thalassemia.