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bioRxiv · 10.1101/2025.05.16.654507

acmgscaler: An R package and Colab for standardised gene-level variant effect score calibration within the ACMG/AMP framework

Badonyi, M.·Marsh, J. A.
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Abstract

SummaryA genome-wide variant effect calibration method was recently developed under the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following ClinGen recommendations for variant classification. While genome-wide approaches offer clinical utility, emerging evidence highlights the need for gene- and context-specific calibration to improve accuracy. Building on previous work, we have developed an algorithm tailored to converting functional scores from both multiplexed assays of variant effects (MAVEs) and computational variant effect predictors (VEPs) into ACMG/AMP evidence strengths. Our method is designed to deliver consistent performance across different genes and score distributions, with all variables adaptively determined from the input data, preventing selective adjustments or overfitting that could inflate evidence strengths beyond empirical support. To facilitate adoption, we introduce acmgscaler, a lightweight R package and a plug-and-play Google Colab notebook for the calibration of custom datasets. This algorithmic framework bridges the gap between MAVEs/VEPs and clinically actionable variant classification. AvailabilityThe package and the Colab notebook are available on GitHub: https://github.com/badonyi/acmgscaler. Supplementary dataSupplementary data can be downloaded from the OSF repository https://osf.io/7hjnm.

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Badonyi, M., Marsh, J. A.. 2025-05-21. acmgscaler: An R package and Colab for standardised gene-level variant effect score calibration within the ACMG/AMP framework. https://doi.org/10.1101/2025.05.16.654507

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