Workshop: Expanding clinical variant interpretation to variants in non-coding regions of the genome

Background: Current guidelines from the American College of Medical Genetics and Genomics and Association of Molecular Pathology (ACMG/AMP) are primarily designed for interpretation of genetic variants that impact protein-coding regions of the genome. We formed an expert panel to design recommendations for how to adapt the ACMG/AMP guidelines for variants in other genomic contexts (Ellingford et al. 2021).

Aim of the workshop: The aim of this interactive workshop is to outline key aspects of the recommendations and detail practical steps towards using the guidance in clinical settings. Users will utilize case examples to develop hands-on working knowledge of the modified guidelines. By the end of the workshop attendees will be able to:

• Understand changes to ACMG/AMP rules. Describe the key adaptations to the ACMG/AMP rules that are needed to effectively curate non-coding region variants and detail the extra considerations applicable when applying individual ACMG/AMP rules.

• Access datasets to define relevant non-coding regions. Understand how to access and interpret the key data and tools required to interpret non-coding region variants. Specifically, you will be familiar with how to access epigenetic data to define non-coding regulatory elements, and will know which in silico tools can be used to predict the pathogenicity of different variant types.

• Perform variant classification for a range of non-coding region variants. Know how to practically approach interpretation of non-coding region variants in your own setting having worked through a series of example curations

Expected prior knowledge / experience: This workshop is aimed at clinical scientists and genetics professionals with an active role in clinical variant interpretation. You will have a working knowledge of the current ACMG/AMP guidelines for small sequence variants.

Format: The workshop will be 90 minutes in length, with approximately 30 minutes spent on each of the three main aims outlined above. The first 30 minutes will be a talk on the background behind and the key aspects of the recommendations. The second 30 minutes will be a demonstration on how to access the tools and resources required to curate non-coding region variants, and the final 30 minutes will be an interactive work-through of example variant curations.

Reference: Ellingford JM et al. medRxiv. Dec 2021. doi:10.1101/2021.12.28.21267792v1