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 tab of the Variant page. It facilitates classification of variant pathogenicity through the automation of 26 out of 28 ACMG criteria and enabling manual review and editing of the tags presented as interactive buttons.

The ACMG SNV Classification Wizard is located in the Evidence section of the Variant Page and is designed to guide users through the interpretation of single nucleotide variants (SNVs) using the ACMG/AMP framework. It automates 26 out of 28 ACMG criteria, with PS4 requiring full manual entry and BS2 partially automated (50% manual).

The ACMG SNV Classification wizard includes a pathogenicity bar that visually represents the pathogenicity score.

The wizard is available for tagged SNVs in disease-associated genes and displays a visual pathogenicity bar summarizing the cumulative 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 tab of the Variant page. Unlike the wizard, automatically assigned criteria and resulting variant class are shown in the Clinical Significance tab 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 a checkbox for selection (1), the criterion 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.

Notes can be added to any tag, and changes are saved using the Save button.

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.

Curate annotation

ACMG tags imported from Curate are indicated by a Curate icon. Curate annotation includes tag status, strength, answered questions, and notes.

The system displays the ACMG classification stored in Curate when all of the following are true:

• The variant has an entry in Curate

• The variant is a SNV

• The variant is tagged by the AI Shortlist in the current Analyze case

• The ACMG schema version in Curate matches the schema active in Analyze

ACMG schema version discrepancy between Analyze and Curate

The ACMG schema defines how evidence is interpreted and how pathogenicity is determined. It is periodically updated to incorporate new ClinGen/ACMG recommendations and platform logic improvements.

If a variant in Curate was classified using an older schema than the one currently active in Analyze:

• The system applies the current schema active in Analyze.

• Curate annotation is not displayed.

• A warning appears in the ACMG SNV Classification wizard.

Whenever a mismatch warning appears:

1. Re‑evaluate the evidence using the current schema.

2. Select Update Curate to update the classification and synchronize schema versions for the variant.

Disease source used in ACMG evaluation

When a gene–disease association is available from multiple databases (for example: OMIM, CGD, Orphanet etc.), the variant page and gene related diseases card display all available disease sources. However, ACMG inheritance-based rules use only the OMIM disease to determine the inheritance mode.

• Multiple disease entries may appear in the UI.

• ACMG logic selects only OMIM entry when determining the inheritance mode.

• If OMIM does not include a pre-populated inheritance mode, ACMG rules that rely on inheritance mode will not be triggered—even if another source (such as CGD) contains this information.

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.