In Silico Analysis of Single Nucleotide Variants of the Nras Gene in Acute Myeloid Leukemia
Year: 2026
Type: article
Abstract: Background Acute myeloid leukemia (AML) is a heterogeneous clonal malignancy of myeloid progenitors. NRAS encodes a small GTPase of the RAS family that regulates signaling pathways involved in cell proliferation, differentiation and survival. Activating missense mutations in NRAS, particularly at hotspot codons 12, 13 and 61, are among the most recurrent genetic alterations in AML. In this context, in silico prediction tools represent a rapid strategy to assess the potential functional impact of single nucleotide variants (SNVs), supporting the prioritization of variants for experimental validation. Aim To identify SNVs of the NRAS gene registered in public databases and predict their potential functional impact using bioinformatic tools, in the context of acute myeloid leukemia. Materials and methods NRAS variants were retrieved from the dbSNP database (Database of Single Nucleotide Polymorphisms) and characterized using UniProt. Variants with the highest global minor allele frequency (MAF) were initially screened; those not corresponding to missense mutations were excluded. A targeted selection of missense SNVs was then performed, and the selected variants were submitted to 13 bioinformatic prediction tools: PredictSNP (integrating SIFT, PolyPhen-1, PolyPhen-2, MAPP, PhD-SNP, SNAP, PANTHER and SNPAnalyzer), iStable (iStable, MuPRO and IMutant) and DynaMut 2.0. Results The dbSNP query identified 6,702 registered variants for NRAS, of which 30 presented population frequency data (MAF). However, the most frequent variants did not correspond to missense mutations, a criterion required for the functional analyses proposed. A targeted selection was therefore performed, and six SNVs (rs14804, rs969273, rs7549358, rs6671984, rs538668088 and rs577550086) were submitted to the functional prediction tools. Discussion Mutations in NRAS are among the most recurrent genetic alterations in acute myeloid leukemia, being frequently reported as missense mutations at hotspot codons 12, 13 and 61, which lead to constitutive activation of the RAS/MAPK signaling pathway and promote uncontrolled proliferation and survival of leukemic cells. In this context, the present in silico screening allowed the prioritization of missense SNVs of NRAS registered in public databases as candidates for functional analysis. Notably, the variants with the highest population frequency were not missense mutations, indicating that population allelic frequency does not necessarily reflect pathogenic relevance in the setting of AML, in which somatic hotspot mutations are the most clinically significant. The use of multiple independent prediction tools increases the reliability of the deleteriousness classification, reducing the bias inherent to individual algorithms. Conclusion The selected NRAS SNVs constitute candidate variants for future experimental validation, contributing to a better understanding of the role of NRAS alterations in the pathogenesis of acute myeloid leukemia. The bioinformatic approach proved adequate for prioritizing variants of potential clinical and biological relevance, and functional assays are warranted to confirm the impact of these variants on leukemogenesis.
Institution: Centro Universitário Nossa Senhora do Patrocínio
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223129211