Logic behind ACMG classification of SNVs
The SNV classification engine applies the joint American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting sequence variants using 28 evidence criteria (PMID: 25741868).
ACMG variant classification
Emedgene applies the ACMG classification guidelines for variant interpretation using the standardized framework established by the American College of Medical Genetics and Genomics (ACMG). This approach is further refined with recommendations from the ClinGen Sequence Variant Interpretation (SVI) Working Group and other expert-reviewed publications to ensure consistent, evidence-based classification of genomic variants.
When assigning a final classification, Emedgene applies the ACMG thresholds using the combination rules described below. See Tag strength adjustments and combination rules for exceptions that affect these combinations.
Pathogenic
1 Very Strong + ≥1 Strong, or
1 Very Strong + ≥2 Moderate, or
1 Very Strong + 1 Moderate + 1 Supporting, or
1 Very Strong + ≥2 Supporting, or
≥2 Strong, or
1 Strong + ≥3 Moderate, or
1 Strong + 2 Moderate + ≥2 Supporting, or
1 Strong + 1 Moderate + ≥4 Supporting.
Likely Pathogenic
1 Very Strong + 1 Moderate, or
1 Very Strong + 1 Supporting, or
1 Strong + 1–2 Moderate, or
1 Strong + ≥2 Supporting, or
≥3 Moderate, or
2 Moderate + ≥2 Supporting, or
1 Moderate + ≥4 Supporting.
Benign
1 Stand-alone — overrides all other tags, or
≥2 Strong.
Likely Benign
1 Strong + 1 Supporting, or
≥2 Supporting.
ACMG variant score
Emedgene calculates the ACMG score for Single Nucleotide Variants (SNVs) using the framework recommended by the American College of Medical Genetics and Genomics (ACMG), along with refinements from ClinGen Sequence Variant Interpretation (SVI) Working Group and other published guidelines (PMID: 32720330).
The software assigns points to each active criterion based on its strength of evidence:
Supporting evidence = 1 point
Moderate evidence = 2 points
Strong evidence = 4 points
Stand-alone or Very Strong evidence = 8 points
The total ACMG score is calculated by adding the points from all pathogenic criteria and subtracting the points from all benign criteria. The result is then interpreted according to these thresholds:
For mtDNA variants, the software excludes the following tags from class calculation: PM1, PM3, PP2, PP5, BP1, BP3, and BP6.
Tag strength adjustments and combination rules
Some ACMG criteria have special handling to ensure consistent scoring in line with expert recommendations:
If PVS1 is combined with any Pathogenic Supporting criterion, the maximum final classification is Likely Pathogenic, not Pathogenic (PM2 SVI Recommendation Ver 1.0, 2020).
If PVS1 is combined with PS1, the combined strength is capped at Very Strong + Supporting (Walker et al., 2023).
If both PVS1 and PP3 are positive, only PVS1 is counted; PP3 is ignored (Abou Tayoun et al., 2018).
If both PVS1 and PM4 are positive, only PVS1 is counted; PM4 is ignored (Abou Tayoun et al., 2018).
If PVS1 and PS1 Supporting are both positive, and another known ClinVar likely pathogenic variant has the same effect at the same splice site, only PVS1 is counted; PS1 is ignored (Walker et al., 2023).
If both PS2 and PM6 are positive, only one is counted, depending on whether de novo status is confirmed (ClinGen SVI WG).
PM2 is assigned Supporting strength by default (PM2 SVI Recommendation Ver 1.0, 2020). You can adjust strength if needed.
If both PM1 and PP3 are positive, the combined strength is capped at Strong, regardless of individual strengths (Pejaver et al., 2022). This prevents inflated scoring when computational evidence overlaps with known mutational hotspot data.
If both PP1 and PP4 are positive, the combined strength is capped at Strong + Supporting, regardless of individual strengths (Biesecker et al., 2024).
PP5 (pathogenic from reputable source) and BP6 (benign from reputable source) are excluded from ACMG score calculation (Biesecker et al., 2018). These can still be displayed for reference but do not affect the classification.
Starting with v100.39.0, you can include PP5 and BP6 in the calculation in the AI ACMG module under Organization settings.
ClinGen gene specifications (v100.39.0+)
When a variant is located in a gene with an existing submission in the ClinGen Criteria Specification (CSpec) Registry, an indication appears in the ACMG section with a link to the CSpec registry. The indication only applies to specifications with the status 'Released'.
The CSpec Registry is intended to provide access to the Criteria Specifications used by ClinGen Variant Curation Expert Panels and biocurators in variant classification.
Warning: Several genes may have multiple specifications, according to association with different diseases.
Disease source used in ACMG evaluation
When a gene–disease association is available from multiple databases (for example: OMIM, CGD, Orphanet etc.), the Gene-related diseases card in the Variant page displays all available disease sources.
Although multiple disease entries may appear, ACMG criteria evaluation logic relies exclusively on the OMIM disease entries when assessing inheritance-dependent evidence.
If OMIM annotation does not include inheritance mode, ACMG rules that depend on inheritance will not be triggered, even if inheritance information exists in another disease source.
The following ACMG SNV criteria are inheritance-dependent and will not be automatically triggered when OMIM inheritance information is missing or differs from other disease sources:
PM2 – Population frequency thresholds depend on whether the disorder is dominant or recessive.
BS1 – Benign frequency evidence is evaluated relative to the expected inheritance mode.
BS2 – Observation in unaffected individuals is interpreted differently for dominant vs recessive conditions.
PP1 / BS4 (Segregation) – Segregation or lack of segregation must match the expected inheritance pattern.
PS2 / PM6 (De novo evidence) – De novo observations are most relevant for dominant or X-linked conditions.
PM3 – Applies only to autosomal recessive disorders and requires an appropriate inheritance context.
BP2 – Allelic configuration (in cis / in trans) is interpreted in relation to the disease inheritance model.
Tracking and traceability of manual changes
The interface tracks and displays all manual modifications to ACMG tags, including changes to tag status, strength, or question responses.
User icon appears on tags, questions, or strength indicators when manually changed. Hover to see the username.
In the Summary tab, tags are color-coded, and manual changes show user icons directly on the tag for quick review.
Emedgene icon indicates the system’s original automated classification. Hover to see the original status or strength.
Curate icon highlights the classification saved in Curate.
Revert button restores tags, strengths, and questions to their last saved state (manual or system-generated).
Learn more
Evidence tab
Return to the Evidence tab overview for related interpretation workflows and tools.
ACMG SNV Classification wizard
Review and edit ACMG tags, strengths, notes, and manual changes for SNVs.
Individual ACMG criteria evaluation
See the detailed logic, thresholds, and evidence sources used for each ACMG criterion.
ACMG CNV Classification wizard
Review the ACMG workflow for CNVs, including automated scoring and manual reclassification.
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