Documentation / Screening / Scoring Components
Scoring Components
Each variant is evaluated across seven independent dimensions. Every component produces a score between 0.0 (no signal) and 1.0 (strongest possible signal). The components are then combined using a weighted sum, where the weights depend on the screening mode and patient age group. See Screening Modes for weight profiles.
Component Overview
| Component | What It Measures | Key Data Sources |
|---|---|---|
| Constraint | Gene intolerance to variation | pLI, LOEUF, missense Z-score |
| Deleteriousness | In-silico pathogenicity prediction | DANN, SIFT, AlphaMissense, MetaSVM, PhyloP, GERP |
| Phenotype | Phenotype match or gene-disease burden | HPO overlap (diagnostic) or HPO count (screening) |
| Dosage | Gene dosage sensitivity | ClinGen haploinsufficiency score |
| Consequence | Variant consequence severity | VEP consequence terms |
| Compound Het | Compound heterozygote potential | Same-gene heterozygous variant pairs |
| Age Relevance | Age-appropriate gene prioritization | Curated gene lists per age group |
1. Constraint Score
Measures how tolerant a gene is to variation using gnomAD constraint metrics. The scoring strategy adapts to the variant's consequence type, because the biological significance of constraint differs between loss-of-function and missense variants.
Loss-of-Function Variants
| Condition | Score |
|---|---|
| pLI > 0.9 AND LOEUF < 0.35 | 1.0 |
| pLI > 0.7 AND LOEUF < 0.5 | 0.8 |
| pLI > 0.5 | 0.6 |
| Otherwise | pLI value directly |
Missense Variants
| Condition | Score |
|---|---|
| mis_z > 3.0 AND pLI > 0.9 | 0.9 |
| mis_z > 2.0 | 0.7 |
| pLI > 0.7 | 0.6 |
| Otherwise | max(pLI, mis_z / 5.0) |
2. Deleteriousness Score
Weighted aggregate of six in-silico pathogenicity predictors. Unlike ACMG classification which uses BayesDel as the single calibrated tool, the screening deleteriousness score combines multiple predictors for a broader assessment of variant impact. This is a ranking signal, not an ACMG evidence criterion.
| Predictor | Weight | Scoring |
|---|---|---|
| DANN | 40% | Raw score (0.0-1.0) |
| SIFT | 15% | 1.0 if Deleterious, 0.0 if Tolerated |
| AlphaMissense | 15% | 1.0 if Pathogenic, 0.5 if Ambiguous, 0.0 if Benign |
| MetaSVM | 15% | 1.0 if Damaging, 0.0 if Tolerated |
| PhyloP | 7.5% | Normalized: score / 10.0, capped at 1.0 |
| GERP | 7.5% | Normalized: score / 6.0, capped at 1.0 |
3. Phenotype Score
How the phenotype score is calculated depends on whether the patient has HPO terms.
| Mode | Calculation |
|---|---|
| Diagnostic (has HPO terms) | Overlap between patient HPO terms and gene HPO associations, divided by total patient terms. |
| Screening (no HPO terms) | Gene-disease burden: HPO count / 10, capped at 1.0. Genes associated with more phenotypes rank higher. |
4. Dosage Score
Based on ClinGen haploinsufficiency curation, applied only to loss-of-function variants. A gene with sufficient evidence for haploinsufficiency means that losing one copy causes disease.
| HI Score | Evidence Level | Dosage Score |
|---|---|---|
| 3 | Sufficient evidence | 1.0 |
| 2 | Emerging evidence | 0.7 |
| 1 | Little evidence | 0.4 |
| Missing or non-LoF | Not applicable | 0.0 |
5. Consequence Score
Severity hierarchy based on the variant's predicted effect on the protein. More disruptive consequences receive higher scores.
| Consequence | Score |
|---|---|
| stop_gained, frameshift, splice_donor, splice_acceptor | 1.0 |
| start_lost, stop_lost | 0.9 |
| inframe insertion/deletion | 0.8 |
| missense | 0.7 |
| splice_region | 0.6 |
| UTR (5' or 3') | 0.4 |
| synonymous | 0.2 |
| intronic | 0.1 |
6. Compound Heterozygote Score
Detects potential compound heterozygotes for autosomal recessive conditions. When two different heterozygous variants occur in the same gene, the patient may have both copies of the gene affected -- one variant on each chromosome.
| Condition | Score |
|---|---|
| Flagged as compound het candidate by classification | 1.0 |
| Heterozygous with another het variant in same gene | 0.8 |
| Not heterozygous or no partner variant | 0.0 |
7. Age Relevance Score
Uses curated gene lists to prioritize age-appropriate disease genes. A BRCA1 variant scores high for an adult but low for a neonate. A CFTR variant scores high for a neonate but moderate for an adult. See Age-Aware Prioritization for the complete gene lists and scoring tables per age group.
Missing Data Handling
All component calculations handle missing data gracefully. When a predictor score is unavailable (NULL), that predictor is excluded from the weighted calculation rather than treated as zero. When gene constraint data is missing, the constraint score defaults to the gene's pLI value or 0.0. This ensures that variants with incomplete annotation are not unfairly penalized or promoted.