2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Determining the impact of rare canonical splice site variants: A comparison of functional and <em>in silico </em>methods

Determining the impact of rare canonical splice site variants: A comparison of functional and in silico methods

Pdf Summary

In this study, the impact of rare canonical splice site variants (CSSVs) on splicing was assessed using RNA sequencing (RNA-seq) data. The researchers aimed to compare the outcomes predicted by in silico tools with the RNA-seq results.<br /><br />It was found that 25% of rare CSSVs did not cause a loss-of-function (LoF) effect, based on the RNA-seq analysis. This suggests that predicting the precise impact of CSSVs without functional studies can be challenging. In fact, the predictions from in silico methods often disagreed with the findings from RNA-seq.<br /><br />These results highlight the need for caution when applying high levels of evidence for pathogenicity (PVS1) to CSSVs in the absence of functional data. The study also acknowledged the limitations of focusing on rare variants in blood expressed genes and using short-read RNA-seq, which may not fully capture the extent of splicing impact.<br /><br />Furthermore, for non-frameshift variants, the impact of rare CSSVs at the protein level remains unclear. This indicates a need for further investigation in this area.<br /><br />Overall, this study emphasizes the importance of functional studies, such as RNA-seq, in determining the impact of CSSVs on splicing. It also suggests that more caution should be exercised when assigning pathogenicity to CSSVs based solely on in silico predictions.

Asset Subtitle

Co-Author - Rachel Oh, MD; Presenting Author - Ali AlMail, BA; Co-Author - Huayun Hou, PhD; Co-Author - Gregory Costain, MD, PhD, FRCPC;

Meta Tag

Bioinformatics

Genomic Methodologies

Sequencing

Co-Author Rachel Oh, MD

Co-Author Huayun Hou, PhD

Co-Author Gregory Costain, MD, PhD, FRCPC

Presenting Author Ali AlMail, BA

Keywords

rare canonical splice site variants

splicing

RNA sequencing

RNA-seq

in silico tools

loss-of-function effect

pathogenicity

functional studies

protein level

caution