ACMG SNV Classification wizard

Where can I review and edit the ACMG Classification of a SNV?

The ACMG SNV Classification wizard is located in the Evidence section of the Variant page. It facilitates classification of variant pathogenicity through the automation of 23 out of 28 ACMG criteria and enabling manual review and editing of the tags presented as interactive buttons.

Starting from version 32.0, the ACMG SNV Classification wizard includes a pathogenicity bar that visually represents the pathogenicity score.

The wizard is available for tagged sequence variants in disease-associated genes. The results of the classification are also highlighted in the Clinical Significance section of the Variant page. Unlike the wizard, automatically assigned criteria and resulting variant class are shown in the Clinical Significance section for all variants in disease-associated genes, regardless of their tagging status.

How do I review and edit the ACMG Classification of a SNV?

Each ACMG tag is represented by an interactive button including checkbox (1), name (2) and evidence strength indicator (3).

Pathogenic criteria are represented by red boxes, while benign criteria boxes are colored green. Each ACMG criterion has three possible states:

• Neutral (1) - represented by an empty checkbox. Criterion requires further investigation.

• Negative (2) - represented by a cross. Criterion is not applicable.

• Positive (3) - represented by a tick and dark color. Criterion is applicable.

Each ACMG tag can be manually checked, unchecked, or set to an undefined state by clicking the interactive button's checkbox element.

To examine in detail or modify the underlying evidence for the particular ACMG tag, select it by clicking on the tag name. The button becomes flood-filled (b), as opposed to it's original, non-selected, state (a).

Upon selection, a description of the criterion and its underlying evidence emerges below. Yes and No radio buttons accompany each piece of evidence. The tag can be assigned if Yes has been selected for all the underlying conditions.

You may modify evidence strength in the Strength dropdown (Stand Alone, Very Strong, Strong, Moderate, Supporting), which will impact both the pathogenicity class and score calculations.

On versions 32.0+, you have the capability to add a note alongside a tag.

After you've modified ACMG classification, you can either save manual changes by pressing the Save button or reset via Revert manual changes. Keep in mind that after saving your edits, Revert manual changes will become unavailable.

ACMG classification of mtDNA variants

The ACMG SNV Classification wizard is available for ACMG classification of tagged mtDNA variants. To classify an mtDNA variant, please manually assign the relevant criteria; the resulting ACMG classification will be calculated automatically.

Seven criteria have been removed in compliance with Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation (2020): PM1, PM3, PP2, PP5, BP1, BP3, BP6.