# tierup `tierup` reanalyses Tier 3 variants in undiagnosed GeL rare disease cases. `tierup` answers the following questions derived from the GeL tiering rules: * Is the variant in a green gene in a panel app panel assigned to the case? * Does the variant mode of inheritance match the gene's in the panel app panel? Tier 3 variants that meet these criteria are labelled 'tier\_1' or 'tier\_2' in the tier\_tierup field of the `tierup` output CSV. ## Installation ```bash pip install jellypy-tierup ``` ## Guides ### Reanalyse Tier 3 variants in a GeL rare disease case 1. Create a configuration file with CIPAPI details. For example: ``` # config.ini [pyCIPAPI] client_id = YOUR-GEL-CLIENT-ID client_secret = YOUR-GEL-CLIENT-SECRET ``` 2. Run tierup For example, interpretation request 1234 version 2 could be analysed with: ```bash tierup --irid 1234 --irversion 1 --config config.ini ``` If the intepretation request data is available locally in json format, then you can pass the file directly: ```bash tierup -j interpretation_request.json --config config.ini ``` 3. View results * \*.tierup.csv - The `tier_tierup` column in the results file contains the new variant tier determined by tierup. Each row is a report event for a variant in the proband. Note: The same variant may have multiple report events depending on the number of assigned gene panels, mode of inheritance and penetrance models analysed. ## TierUp output fields (\*.tierup.csv) | Field | Description | | --------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------- | | interpretation\_request\_id | Identifier for GeL case | | tier\_tierup | Tiering result from tierup: tier\_3\_not\_in\_panel, tier\_3\_red\_or\_amber, tier\_3\_green\_moi\_mismatch, tier\_2, tier\_1 | | tier\_gel | Initial GeL tier. Previously *tier* field in tierup 0.2.0 | | assembly | Reference genome | | chromosome | Chromosome number | | position | Genomic coordinate | | reference | Reference allele | | alternate | Proband Alternate allele | | consequences | Sequence ontology terms for the variant consequences in all relevant transcripts | | zygosity | Zygosity in the proband | | segregation | Pattern calculated using genotypes from family members | | penetrance | Penetrance model used to assess the variant | | tiering\_moi | Mode of inheritance for the variant in the proband. Previously *inheritance* field in tierup 0.2.0 | | tu\_panel\_hash | Panel unique hash id used in TierUp analysis | | tu\_panel\_name | Panel name used in TierUp analysis | | tu\_panel\_version | Panel version used in TierUp analysis | | tu\_panel\_number | Panel id used in TierUp analysis | | tu\_panel\_created | The date the panel version used in TierUp analysis was created | | tu\_run\_time | Time TierUp was initiated | | pa\_ensembl | Ensembl identifier for the gene in panelapp panel | | pa\_hgnc\_id | HGNC ID from the panel app panel | | pa\_gene | Gene symbol from the panel app panel | | pa\_moi | Mode of inheritance for the gene in the panelapp panel version | | pa\_confidence | Current gene confidence level from the latest version of the panel app panel: 4 or 3 = Green; 2 = Amber; 1 or 0 = Red; Green genes indicate TieredUp variant. | | extra\_panels | Panel ID pointers updated via TierUp check for depreciated Panels in GeL directory | | re\_id | Unique identifier for the report event. Previously *event\_id* field in tierup 0.2.0 | | re\_panel\_id | Report event panel id | | re\_panel\_version | Report event panel version | | re\_panel\_source | Report event panel source. All expected to be panelapp | | re\_panel\_name | Report event panel name | | re\_gene | Report event gene symbol | | justification | GeL eventJustification field which describes why the variant was tiered | | created\_at | Creation date for the GeL interpreted genome was created | | software\_versions | Software versions used in the GeL analysis | | reference\_db\_versions | Reference database versions used int he GeL analysis | | tu\_version | jellypy-tierup version used to generate results | ## Constraints * `tierup` input is limited to undiagnosed rare disease cases. The tool therefore raises an error if users attempt to process a solved case. * Access to case data from GeL is only possible on the [HSCN](https://digital.nhs.uk/services/health-and-social-care-network) * Interpretation request data must comply with the GeL v6 interpretation request model * `tierup` does not analyse CNVs * `tierup` does not account for information on variant penetrance ## Support Please [raise issues](https://github.com/NHS-NGS/JellyPy), message the [#jellypy slack](https://binfx.slack.com/messages) channel or [send an email](mailto:nana.mensah1@nhs.net). --- # Agent Instructions: Querying This Documentation If you need additional information that is not directly available in this page, you can query the documentation dynamically by asking a question. Perform an HTTP GET request on the current page URL with the `ask` query parameter: ``` GET https://acgs.gitbook.io/jellypy/tierup.md?ask= ``` The question should be specific, self-contained, and written in natural language. The response will contain a direct answer to the question and relevant excerpts and sources from the documentation. Use this mechanism when the answer is not explicitly present in the current page, you need clarification or additional context, or you want to retrieve related documentation sections.