1. OverviewΒΆ

Trio Tutorial

This tutorial will cover a trio analysis that includes importing VCF files, annotating and filtering variants, and rendering a clinical report using the ACMG Guidelines. The sample data includes a Yoruban trio from the HapMap Project with Mother-NA12938, Father-NA12939, and Proband-NA12940. Using this pedigree structure we will identify variants of different inheritance structures and evalute them using VSClinical according to the ACMG Guidelines.

VarSeq VSClinical ACMG

VSClinical is a tool that provides a simple way to leverage all the available evidence for a variant and score it for the potential impact it has on a disorder. The available evidence can be categorized into groups which includes considerations for gene function/phenotype association, variant segregation in a family, results of running variants through prediction algorithms or their presence in databases, but also utilizing previous discoveries you yourself have made for any variant.

This collection of evidence is then linked to 33 criteria that the user can efficiently assess in a streamlined effort. These criteria are then aggregated to provide the basis for the final classifications of pathogenic, likely pathogenic, uncertain significance, likely benign or benign. When considering the amount of available evidence and requirements for eventually classifying variants, this process can become complex and difficult to master. Fortunately, VSClinical is a solution to this complexity. VSClinical provides a means of simplifying not only the process of scoring and classifying variants, but also provides a simple yet sophisticated means of presenting all evidence and criteria visually.

Pathognic Scale

Figure 1-1: Pathogenic and benign classification scale.

This tutorial walks the user though a trio analysis workflow with focus on the ACMG guidelines starting with a template provided by Golden Helix and ending with a clinical report. We will first cover the import steps and explore the filtering logic then we will use the ACMG Classifier to evaluate selected variants and render a clinical report. This tutorial was accompanied by three VCF samples contained in a ZIP file, which you will need to download and extract to a convenient location.