Documentation / Screening / Tier System
Tier System
After scoring, every variant is assigned to one of four priority tiers. Tier assignment considers both the total weighted score and individual component peaks -- a single exceptional signal can elevate a variant to Tier 1. Clinical boosts from patient context can further promote variants to higher tiers.
Tier Definitions
Immediate clinical review required. These variants have the strongest evidence for clinical relevance to this patient. Tier 1 is capped at 20 variants by default to keep the review set manageable.
Should be reviewed if time permits. These variants have moderate evidence for clinical relevance and may become Tier 1 with additional clinical information.
Future consideration. These variants have weak evidence for immediate clinical relevance but may be worth monitoring for reclassification or new evidence.
Likely not clinically relevant. Excluded from results by default. Can be included via settings for comprehensive review.
Base Tier Assignment
The base tier is determined from the weighted total score and individual component peaks. Peak-based promotion ensures that a single exceptional signal (for example, a highly constrained gene with pLI = 0.99) elevates a variant to Tier 1 even if other components are moderate.
| Tier | Condition |
|---|---|
| Tier 1 | Total score >= 0.80, OR any of constraint / dosage / deleteriousness / age_relevance >= 0.9 |
| Tier 2 | Total score >= 0.50 |
| Tier 3 | Total score >= 0.20 |
| Tier 4 | Total score < 0.20 |
Clinical Boosts
After base scoring, patient-specific clinical context adds priority boosts. Boosts are additive to the base score and capped at a total of 1.0. These boosts can promote variants to higher tiers than their base score alone would justify.
| Boost | Condition | Amount |
|---|---|---|
| ACMG Class | Pathogenic classification | +0.30 |
| ACMG Class | Likely Pathogenic classification | +0.20 |
| Phenotype Tier | Tier 1 phenotype match | +0.25 |
| Phenotype Tier | Tier 2 phenotype match | +0.15 |
| Family History | Cancer gene + family history | +0.25 |
| Family History | Cardiac gene + family history | +0.20 |
| Sex-Linked | X-linked gene in male patient | +0.30 |
| Sex-Linked | X-linked gene in female patient | +0.10 |
| Consanguinity | Homozygous variant + consanguinity | +0.25 |
| Ethnicity | Ashkenazi Jewish founder gene | +0.15 to +0.20 |
| De Novo | Trio sample in highly constrained gene | +0.20 |
| Pregnancy | Prenatal actionable gene + pregnant | +0.20 |
Final Tier Promotion
After all boosts are applied, the final tier is recalculated. Certain conditions guarantee Tier 1 placement regardless of the base score:
| Final Tier | Condition |
|---|---|
| Tier 1 | Any Pathogenic or Likely Pathogenic variant (ACMG boost > 0) |
| Tier 1 | Tier 1 phenotype match (phenotype boost >= 0.25) |
| Tier 1 | Boosted score >= 0.70 |
| Tier 2 | Tier 2 phenotype match OR boosted score >= 0.50 |
| Tier 3 | Boosted score >= 0.20 |
| Tier 4 | Boosted score < 0.20 |
Clinical Actionability Labels
Each variant also receives a clinical actionability label indicating the recommended clinical response:
| Label | Criteria |
|---|---|
| Immediate | Pathogenic or Likely Pathogenic in an ACMG Secondary Findings gene (81 genes including BRCA1/2, MYBPC3, KCNH2, LDLR) |
| Monitoring | Pathogenic or Likely Pathogenic in other gene, or total score > 0.7 |
| Future | Total score > 0.4 |
| Research | Everything else |