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

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:

    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:

    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‚Äč

  • 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, message the #jellypy slack channel or send an email.