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Description 

The Genomics England Rare Disease Tiering Process is to aid NHS GMC evaluation of Rare Disease primary finding results by annotating variants that are plausibly pathogenic based on their segregation in the family, frequency in control populations, effect on protein coding, mode of inheritance, and whether they are in a gene in the virtual gene panel(s) applied to the family. The process is summarised in the figure below. 


During the Tiering process, variants (which have been previously called, normalised, and annotated by the Rare Disease Interpretation Pipeline) pass through multiple filters (allele frequency, consequence type, segregation, quality etc.) in order to classify those that are potentially relevant/causal for a specific case and disease. 

A similar process is also used to classify variants in the Cancer Programme. The implementation of Tiering for the two programmes are very different. This documentation is focused only on the Tiering process for Rare Disease. 

Variants of potential relevance to the patient’s clinical presentation will be automatically categorised into three Tiers: 

TIER 1: Should be clinically assessed by NHS GMCs. Includes, high impact variants (e.g. likely loss-of function) and de novo moderate impact variants (e.g. missense) within a curated list of genes available through PanelApp with sufficient evidence associating them with the patient’s phenotype(s). In the future it is anticipated Tier 1 will contain known pathogenic variants once a high confidence curated list has been generated.

TIER 2: Should be clinically assessed by NHS GMCs. Includes moderate impact variants (e.g. missense) within a curated list of genes available through PanelApp with sufficient evidence associating them with the patient’s phenotype(s).

TIER 3: It is not expected that NHS GMCs will review all of the variants in Tier 3. Plausible candidate variants identified in genes OUTSIDE of known disease gene panel(s), caution should be used during clinical assessment and interpretation. 
Includes high and moderate impact variants outside of the curated list of genes that are associated with the patient’s phenotype(s). Although most tier 3 variants will NOT be pathogenic, sometimes the causal variant will lie within tier 3. This could occur because there is insufficient evidence to support the inclusion of the gene within the relevant panel(s) at the time of analysis, or because the relevant panel was not applied.

You can learn more about the Tiering algorithm in the Rare Disease Results Guide and FAQ on the Tiering Data

Location

Tiering data

Tiered variants for interpreted rare disease families can be found within the LabKey table, tiering_data. Within this table, one can filter variants by: Tier (Tier 1, Tier 2, Tier 3), chromosomal position, gene name, variant consequence type, genotype, and phenotype, as well as other variables. One can also browse the raw Tiering data in the Interpretation Request file. 

Allele frequency of tiered variants

The LabKey table, tiered_variants_frequency, displays the allele frequency of all Tiered variants in various cohorts. The allele frequency data are kept in a separate table in LabKey as the data are too large. 

Gene panels applied

The LabKey table, panels_applied, displays the gene panels applied to the family during the Tiering process and the panel version. You can browse all panels and versions here: https://panelapp.genomicsengland.co.uk/


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