IN-SILICO CHARACTERISATION OF PATHOGENIC MISSENSE SNPS IN HUMAN FLT3 GENE

Abstract

FLT3 gene (FMS like tyrosine kinase): encodes a receptor tyrosine kinase protein that regulates the differentiation of stem and progenitor cells , and genetic alteration in this gene often causes acute myeloid leukaemia and autoimmune conditions like rheumatoid arthritis. Non-synonymous single-nucleotide polymorphisms (nsSNPs), or missense variants, can critically change the function of the FLT3 protein by keeping it constitutively active, potentially contributing to disease development. This study utilized a in-silico approach to evaluate the functionally deleterious nsSNPs in the human FLT3 gene. A dataset of 1,444 missense variants was sourced from theNCBI dbSNP database, and five tools (SIFT, PolyPhen-2, FATHMM, SNPs3D, RegulomeDB) were used for initial screening. High-risk variants were further validated using MutPred2, CADD, and ClinPred to confirm their deleterious potential. The impact on protein stability and evolutionary conservation was checked using I Mutant 2.0 and ConSurf. Ten nsSNPs (F349L, A680V, A814S, D829E, D835E, D835V, I836M, Y842C, R849H, I881T) were consistently predicted as deleterious and validated as pathogenic. I-Mutant 2.0 predicted mutations out of which 7 destabilise protein and rest stabilise, and ConSurf analysis revealed that all except F349L are located at highly conserved residues, indicating their critical structural or functional roles. The ten potentially damaging, high-risk nsSNPs in FLT3 identified in this work are likely to alter the functioning and structure of proteins, offering a solid basis for further experimental verification and supporting the creation of tailored treatments for disorders linked to FLT3.