protPheMut: An Interpretable Machine Learning Tool for Classification of Cancer and Neurodevelopmental Disorders in Human Missense Variants

Publication date: Jan 06, 2025

Motivation: Recent advances in human genomics have revealed that missense mutations in a single protein can lead to distinctly different phenotypes. In particular, some mutations in oncoproteins like Ras, MEK, PI3K, PTEN, and SHP2 are linked various cancers and Neurodevelopmental Disorders (NDDs). While numerous tools exist for pre-dicting the pathogenicity of missense mutations, linking these variants to certain phenotypes remains a major chal-lenge, particularly in the context of personalized medicine. Results: To fill this gap, we developed protPheMut (Protein Phenotypic Mutations Analyzer), leveraging multiple in-terpretable machine learning methods and integrate diverse biophysics and network dynamics-based signatures, for the prediction of mutations of the same protein can promote cancer, or NDDs. We illustrate the utility of protPheMut in phenotypes (cancer/NDDs) prediction by the mutation analysis of two protein cases, that are PI3K and PTEN. Compared to seven other predictive tools, protPheMut demonstrated exceptional accuracy in forecasting phenotypic effects, achieving an AUROC of 0.8501 for PI3K mutations related to cancer and Cowden syndrome. For multi-phenotypes prediction of PTEN mutations related to cancer, PHTS, and HCPS, protPheMut achieved an AUC of 0.9349 through micro-averaging. Using SHAP model explanations, we gained insights into the mechanisms driving phenotype formation. A user-friendly website deployment is also provided.

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Concepts Keywords
202410285264y Al
Cancer Cowden
Entrepreneurship Hcps
Misclassified Missense
Pi3_pi4_kinase Mutation
Mutations
Network
Phenotypes
Phenotypic
Phts
Pi3k
Protphemut
Pten
Related
Syndrome

Semantics

Type Source Name
disease MESH Cancer
disease MESH Neurodevelopmental Disorders
drug DRUGBANK Rasagiline
disease MESH Cowden syndrome
drug DRUGBANK Activated charcoal
disease MESH Infectious Diseases
disease MESH Laboratory Infection
drug DRUGBANK L-Phenylalanine
drug DRUGBANK Coenzyme M
disease MESH abnormalities
disease MESH autism spectrum disorder
disease MESH neurofibromatosis
disease MESH Noonan syndrome
disease MESH syndrome
disease MESH central nervous system tumors
drug DRUGBANK Spinosad
drug DRUGBANK Trestolone
disease MESH pathogenesis
drug DRUGBANK Flunarizine
drug DRUGBANK Pidolic Acid
disease MESH confusion
drug DRUGBANK Saquinavir
disease MESH phenotypic variations
disease MESH Hypophosphatasia
drug DRUGBANK Potassium

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