Predicting the impact of rare variants on RNA splicing in CAGI6

Author:

Lord JennyORCID,Oquendo Carolina Jaramillo,Wai Htoo A.,Douglas Andrew G. L.,Bunyan David J.,Wang Yaqiong,Hu Zhiqiang,Zeng Zishuo,Danis Daniel,Katsonis Panagiotis,Williams Amanda,Lichtarge Olivier,Chang Yuchen,Bagnall Richard D.,Mount Stephen M.,Matthiasardottir Brynja,Lin Chiaofeng,Hansen Thomas van Overeem,Leman Raphael,Martins Alexandra,Houdayer Claude,Krieger Sophie,Bakolitsa Constantina,Peng Yisu,Kamandula Akash,Radivojac Predrag,Baralle Diana

Abstract

AbstractVariants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant’s impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact. The performance of 12 prediction methods, along with SpliceAI and CADD, was compared on the 56 functionally validated variants. The maximum accuracy achieved was 82% from two different approaches, one weighting SpliceAI scores by minor allele frequency, and one applying the recently published Splicing Prediction Pipeline (SPiP). SPiP performed optimally in terms of sensitivity, while an ensemble method combining multiple prediction tools and information from databases exceeded all others for specificity. Several challenge methods equalled or exceeded the performance of SpliceAI, with ultimate choice of prediction method likely to depend on experimental or clinical aims. One quarter of the variants were incorrectly predicted by at least 50% of the methods, highlighting the need for further improvements to splicing prediction methods for successful clinical application.

Funder

NIHR

New South Wales Health

University of Southampton

Publisher

Springer Science and Business Media LLC

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