PGx Allele Definitions and PGx Guidelines

PGx Allele Definitions and PGx Guidelines

DRAGEN Array star allele calling leverages the star allele definitions provided by PharmVar and PharmGKB. DRAGEN Array star allele phenotype annotation, using the “star-allele annotate” command, is achieved through direct lookup into public PGx guidelines CPIC or DPWG, which is selected by the user when running DRAGEN Array.

See table below for details of the data sources.

Data Source	Version	URL
PharmVar	6.1	https://www.pharmvar.org
PharmGKB	Snapshot-2024.05.16	https://www.pharmgkb.org/
UGT Alleles Nomenclature	2010.12.21	https://www.pharmacogenomics.pha.ulaval.ca/ugt-alleles-nomenclature/
Human Cytochrome P450 (CYP) Allele Nomenclature Database Legacy Content	July 2024	https://www.pharmvar.org/htdocs/archive/index_original.htm
CPIC guidelines	1.38.0	https://cpicpgx.org/guidelines/ https://github.com/cpicpgx/cpic-data/
DPWG guidelines	June 2023	https://www.pharmgkb.org/page/dpwgMapping

DRAGEN Array “star-allele annotate” command provides both metabolizer status and activity score annotations for genes covered by the CPIC and DPWG guidelines.

Specifically, CPIC metabolizer/phenotype annotations are supported for CACNA1S, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, G6PD, MT-RNR1, NUDT15, RYR1, SLCO1B1, TPMT, UGT1A1, CFTR, IFNL3/IFNL4 and VKORC1, among them activity scores are supported for CYP2C9, CYP2D6, and DPYD. DPWG metabolizer/phenotype annotations are supported for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, NUDT15, SLCO1B1, TPMT, UGT1A1, VKORC1 and F5, among them activity scores are supported for CYP2D6 and DPYD.

Extended Multi-allelic variants based on the designs in the supported PGx products

• DRAGEN Array PGx extends any single allele variant definitions obtained from PharmVar or PharmGKB that have multiple alleles in Illumina's product files to include all alleles of the Multi Allelic Variant (MAV). The table below shows the MAVs that were extended in the DRAGEN Array Database to cover all alleles for that MAV that are in the product files. Allele Name describes the allele that was added to the database.

Gene Symbol	Allele Name	Hgvs
CACNA1S.rs1800559	rs1800559.C>A	NC_000001.11:g.201060815C>A
CFTR.rs113993958	rs113993958.G>A	NC_000007.14:g.117530953G>A
CFTR.rs113993958	rs113993958.G>T	NC_000007.14:g.117530953G>T
CFTR.rs11971167	rs11971167.G>T	NC_000007.14:g.117642528G>T
CFTR.rs121908755	rs121908755.G>T	NC_000007.14:g.117587800G>T
CFTR.rs121909005	rs121909005.T>C	NC_000007.14:g.117587801T>C
CFTR.rs121909020	rs121909020.G>C	NC_000007.14:g.117611640G>C
CFTR.rs150212784	rs150212784.T>C	NC_000007.14:g.117611595T>C
CFTR.rs193922525	rs193922525.G>C	NC_000007.14:g.117664770G>C
CFTR.rs267606723	rs267606723.G>T	NC_000007.14:g.117642451G>T
CFTR.rs397508288	rs397508288.A>C	NC_000007.14:g.117590409A>C
CFTR.rs397508759	rs397508759.G>T	NC_000007.14:g.117534363G>T
CFTR.rs74551128	rs74551128.C>T	NC_000007.14:g.117548795C>T
CFTR.rs75039782	rs75039782.C>G	NC_000007.14:g.117639961C>G
CFTR.rs77834169	rs77834169.C>A	NC_000007.14:g.117530974C>A
CFTR.rs77834169	rs77834169.C>G	NC_000007.14:g.117530974C>G
CFTR.rs77932196	rs77932196.G>C	NC_000007.14:g.117540270G>C
CFTR.rs77932196	rs77932196.G>T	NC_000007.14:g.117540270G>T
CFTR.rs78655421	rs78655421.G>C	NC_000007.14:g.117530975G>C
CFTR.rs78655421	rs78655421.G>T	NC_000007.14:g.117530975G>T
COMT.rs13306278	rs13306278.C>G	NC_000022.11:g.19941504C>G
DPYD.rs114096998	rs114096998.2.G>C	NC_000001.11:g.97078987G>C
DPYD.rs140602333	rs140602333.G>T	NC_000001.11:g.97573919G>T
DPYD.rs142619737	rs142619737.C>G	NC_000001.11:g.97515851C>G
DPYD.rs143154602	rs143154602.G>T	NC_000001.11:g.97593289G>T
DPYD.rs145548112	rs145548112.C>A	NC_000001.11:g.97306195C>A
DPYD.rs190951787	rs190951787.G>T	NC_000001.11:g.97515889G>T
DPYD.rs200687447	rs200687447.2.C>A	NC_000001.11:g.97193209C>A
DPYD.rs3918289	rs3918289.G>A	NC_000001.11:g.97450059G>A
DPYD.rs3918290	rs3918290.C>G	NC_000001.11:g.97450058C>G
DPYD.rs6670886	rs6670886.C>A	NC_000001.11:g.97699506C>A
DPYD.rs72549304	rs72549304.G>C	NC_000001.11:g.97549609G>C
DPYD.rs72549304	rs72549304.G>T	NC_000001.11:g.97549609G>T
DPYD.rs748620513	rs748620513.C>A	NC_000001.11:g.97573799C>A
DPYD.rs748639205	rs748639205.A>G	NC_000001.11:g.97082415A>G
DPYD.rs760663364	rs760663364.G>C	NC_000001.11:g.97515928G>C
DPYD.rs777425216	rs777425216.C>A	NC_000001.11:g.97515815C>A
RYR1.38499667G>A	NC_000019.10:g.38499667G>T	NC_000019.10:g.38499667G>T
RYR1.rs118192116	rs118192116.C>T	NC_000019.10:g.38451850C>T
RYR1.rs118192151	rs118192151.G>C	NC_000019.10:g.38584974G>C
RYR1.rs118204423	rs118204423.G>A	NC_000019.10:g.38457539G>A
RYR1.rs142474192	rs142474192.G>T	NC_000019.10:g.38443790G>T
RYR1.rs143988412	rs143988412.A>G	NC_000019.10:g.38580066A>G
RYR1.rs1801086	rs1801086.G>T	NC_000019.10:g.38446710G>T
RYR1.rs186983396	rs186983396.C>G	NC_000019.10:g.38442434C>G
RYR1.rs193922762	rs193922762.C>A	NC_000019.10:g.38448673C>A
RYR1.rs193922767	rs193922767.G>A	NC_000019.10:g.38452996G>A
RYR1.rs193922772	rs193922772.G>A	NC_000019.10:g.38457546G>A
RYR1.rs193922826	rs193922826.C>G	NC_000019.10:g.38504319C>G
RYR1.rs193922838	rs193922838.G>A	NC_000019.10:g.38529036G>A
RYR1.rs193922842	rs193922842.C>T	NC_000019.10:g.38543821C>T
RYR1.rs370634440	rs370634440.G>T	NC_000019.10:g.38463499G>T

Exceptions to Star Allele Definitions

G6PD

With the changes of reference genomes, the definition for a star allele sometimes need to be updated accordingly.

Mediterranean Haplotype and Mediterranean, Dallas, Panama, Sassari, Cagliari, Birmingham are defined by two variants rs5030868 and rs2230037. In genome build GRCh37, Mediterranean Haplotype is defined by rs2230037 G>A and rs5030868 G>A, and Mediterranean, Dallas, Panama, Sassari, Cagliari, Birmingham is defined by rs5030868 G>A, with rs2230037 reference allele G.

In genome build GRCh38, Mediterranean Haplotype is defined by rs5030868 G>A, with rs2230037 reference allele A, and Mediterranean, Dallas, Panama, Sassari, Cagliari, Birmingham is defined by rs2230037 A>G and rs5030868 G>A.

Variant rs2230037 is ignored in all other G6PD alleles except in the two Mediterranean alleles.