Tiering algorithm¶
A simplified view of the approach taken during tiering is included in the Overview. The Tiering algorithm considers variants or groups of variants in relation to eight criteria, each of which is further elaborated in separate sections:
- FILTER status
- Population frequency
- Predicted functional impact
- Segregation with disease in the recruited family
- (a) Intersection with a high-evidence Green gene on the specified gene panel(s) AND (b) match with the curated mode of inheritance, as detailed in PanelApp
- Known pathogenic/likely pathogenic disease associations
- Internal and/or stakeholder knowledgebase of variant pathogenicity (small variant inclusion list)
- Internal and/or stakeholder knowledgebase of variant benignity or artefacts
The table below summarises the relationship between the eight criteria and the assigned Tier groups:
| Assumption | Tier 1 | Tier 2 | Tier 3 | Untiered |
|---|---|---|---|---|
| If a variant or group of variants does not pass all of criteria 1-4 |  |
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| If a variant (group) passes all criteria 1-4 but does not pass 5(a) | |
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| If a variant (group) passes all of criteria 1-4 and 5(a) but not 5(b) | |
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| If a variant (group) passes all of criteria 1-5 and if predicted high impact consequence type OR a de novo variant with predicted functional impact (high, moderate, or in a non-coding gene) | |
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| If a variant (group) passes all of criteria 1-5 and if not predicted high impact consequence type (excluding de novo variants) | |
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| If a variant (group) passes criteria 1, 4, 5 and 6 | |
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| If a variant (group) passes criteria 1, 4 and 6 but not 5(a) | |
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| If a variant (group) passes criteria 1, 4, 5(a) and 6 but not 5(b) | |
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| If a variant (group) passes criteria 1, 4, 5 and 7 | |
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| If a variant (group) passes criteria 1, 4 and 7 but not 5(a) | |
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| If a variant (group) passes criteria 1, 4, 5(a) and 7 but not 5(b) | |
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| If a variant (group) passes criteria 8 | |
Variants that fail criteria 1-4, or pass critera 1-4 and are in a green gene but fail 5a will be Untiered
The Tiering pipeline analyses any family structure (by organising participants in trios of mother, father and offspring), regardless of the complexity of pedigree. All the trios must pass the defined filters. Where a family trio cannot be constructed, subsets are considered, such as parent-child pairs.
Where multiple gene panels have been assigned to a family, Tiering is performed independently using each panel.