Illumina Connected Annotations

Illumina Connected Annotations, also known as Illumina Annotation Engine (IAE) or Nirvana provides translational research-grade annotation of genomic variants (SNVs, MNVs, insertions, deletions, indels, STRs, gene fusions, and SVs (including CNVs). It is bundled with DRAGEN and provides comprehensive variant annotation capabilities. You can annotate VCF files either:

Automatically through DRAGEN pipeline parameters
Manually using the standalone Illumina Connected Annotations tool

The input to Illumina Connected Annotations are VCFs and the output is either a structured JSON representation of all annotation and sample information (as extracted from the VCF) or an annotated VCF. Please note that the annotated VCF only contains a subset of the annotations provided in the JSON output. This tool can handle multi-sample VCFs.

Key Requirements

Before annotating variants, you must:

Configure credentials for premium data sources
Download annotation data files
Specify the data location when running DRAGEN or the standalone tool

Installation Paths

The annotation binaries location depends on your DRAGEN environment:

Environment

Nirvana Path

Resource Path

On-Premise

/opt/dragen/<DRAGEN_VERSION>/share/nirvana/

/opt/dragen/<DRAGEN_VERSION>/resources/annotation/

Cloud

/opt/edico/share/nirvana/

/opt/edico/resources/annotation/

Available binaries:

Nirvana: Illumina Connected Annotations tool
DataManager: Annotation data download manager

Platform Compatibility

Nirvana and DataManager are compatible with CentOS 7, Oracle 8, and other modern Linux distributions using x64 processors.

Downloading Annotation Data Files

Variant annotation in DRAGEN requires additional annotation data files that have to be downloaded prior to running any DRAGEN pipeline that requires variant annotation. To download, please use the DataManager software that is located in <INSTALL_PATH>/share/nirvana/DataManager.

Detailed instructions on how to setup annotations is available here. We highly recommend using the Automated Script Setup.

Detailed Instructions

If you prefer not to use the automated script, please follow the instructions here.

Annotate Files (via DRAGEN command-line)

To automatically annotate output VCFs, please add the following command-line arguments:

Parameter

Value

Description

--enable-variant-annotation

true

Enables variant annotation

--variant-annotation-data

/path/to/data/directory

Location of downloaded annotation files

--variant-annotation-assembly

GRCh37 or GRCh38

Reference genome assembly (use GRCh37 for hg19)

--annotation-data-config

/path/to/data/versions-config-json

File path to annotation data config (json) file, if this is not set, embedded data config will be used

--variant-annotation-assembly

true

Set Nirvana output format to VCF(optional)

All the command-line arguments shown together:

dragen \
  --enable-variant-annotation true \
  --variant-annotation-data /data/nirvana_data \
  --variant-annotation-assembly GRCh38 \
  --annotation-data-config /opt/dragen/<DRAGEN_VERSION>/resources/annotation/latest_annotations_GRCh38.json \
  --variant-annotation-enable-vcf-output true \
  [... other DRAGEN parameters ...]

Annotate Files (via standalone Illumina Connected Annotations)

Please note that Illumina Connected Annotations supports uncompressed VCF files and bgzip compressed VCF files. VCF files that have been compressed by standard gzip are not supported.
To annotate the file, enter the following command:

/<NIRVANA PATH>/Nirvana \
  -i <input.vcf> \
  -o <output_prefix> \
  -c <data_dir>/Cache \
  -r <data_dir>/References/Homo_sapiens.GRCh38.Nirvana.dat \
  --sd <data_dir>/SupplementaryAnnotation/GRCh38 \
  -l <credentials.json> \
  --versions-config /opt/dragen/<DRAGEN_VERSION>/resources/annotation/all_annotations_GRCh38.json

Parameters:

Option

Description

Example

-i

Input VCF file (uncompressed or bgzipped)

input.vcf.gz

-o

Output file prefix

output

-c

Cache directory

/data/nirvana_data/Cache

-r

Reference file

/data/nirvana_data/References/Homo_sapiens.GRCh38.Nirvana.dat

--sd

Supplementary annotation directory

/data/nirvana_data/SupplementaryAnnotation/GRCh38

-l

Credentials file

credentials.json

--versions-config

Version configuration file

Path from resources directory

Using the example above, Annotations generates the following output.

---------------------------------------------------------------------------
Illumina Connected Annotations                      (c) 2026 Illumina, Inc.
                                                                     3.27.0
---------------------------------------------------------------------------

Data Source              Type                     Status    Comments
---------------------------------------------------------------------------
DANN                     Score                    Loaded    20200205
DECIPHER                 StructuralVariant        Loaded    201509
Ensembl                  GeneModels               Loaded    112
FusionCatcher            GeneFusion               Loaded    1.33
GME                      SmallVariant             Loaded    20160618
GenomeAssembly           GenomeAssembly           Loaded    GRCh38.p14
Gerp                     Score                    Loaded    20110522
HGNC                     GeneModels               Loaded    20240603
MultiZ100Way             Protein                  Loaded    20171006
PrimateAI                SmallVariant             Loaded    0.2
PromoterAI               SmallVariant             Loaded    1.0
REVEL                    SmallVariant             Loaded    20200205
RefSeq                   GeneModels               Loaded    GCF_000001405.40-RS_2023_10
TOPMed                   SmallVariant             Loaded    freeze_5
clingen                  Gene                     Loaded    20240910
clingen                  StructuralVariant        Loaded    20240910
clingen (legacy)         StructuralVariant        Loaded    20160414
clinvar                  SmallVariant             Loaded    20240902
clinvar                  StructuralVariant        Loaded    20240902
clinvar-preview          SmallVariant             Loaded    20240902
clinvar-preview          StructuralVariant        Loaded    20240902
cosmic                   Gene                     Loaded    99
cosmic                   GeneFusion               Loaded    99
cosmic                   SmallVariant             Loaded    99
dbSNP                    SmallVariant             Loaded    156
globalAllele             SmallVariant             Loaded    151
gnomad                   Gene                     Loaded    4.1
gnomad                   LowComplexityRegions     Loaded    2.1
gnomad                   SmallVariant             Loaded    4.1
gnomad                   StructuralVariant        Loaded    4.1
gnomad-exome             SmallVariant             Loaded    4.1
mitomap                  SmallVariant             Loaded    20200819
mitomap                  StructuralVariant        Loaded    20200819
omim                     Gene                     Loaded    20240910
oneKg                    RefMinor                 Loaded    Phase 3 v3plus
oneKg                    SmallVariant             Loaded    Phase 3 v3plus
oneKg                    StructuralVariant        Loaded    Phase 3 v5a
phylopScore              ConservationScore        Loaded    hg38
phylopScore              Score                    Loaded    1.0
primateAI-3D             SmallVariant             Loaded    1.0
spliceAI                 SmallVariant             Loaded    1.3
---------------------------------------------------------------------------

Initialization                                         Time     Positions/s
---------------------------------------------------------------------------
Cache                                               00:00:03.6
SA initialization                                   00:00:08.0
VCF Position Scan                                   00:00:00.0      115,442

Reference                             SA Loading    Annotation   Variants/s
---------------------------------------------------------------------------
chr1                                    00:00:00.5  00:00:02.0        4,980

Summary                                                Time         Percent
---------------------------------------------------------------------------
Initialization                                      00:00:11.7       84.9 %
Annotation                                          00:00:02.0       14.4 %
 |--SA Loading                                      00:00:00.5        4.2 %
 |--Output writing                                  00:00:00.3        2.2 %
License Check                                       00:00:00.0        0.0 %
Usage Report                                        00:00:00.0        0.0 %
---------------------------------------------------------------------------
Gross Annotation rate:                                  718.84 positions/sec

Peak memory usage: 5.867 GB
Time: 00:00:13.8

Note For complete annotation options, see the Illumina Connected Annotations guide.

JSON Output File

Annotations produces an output file in JSON format. Please refer to Illumina Connected Annotations JSON for detailed description of the JSON file.

Version History

Annotations binaries have been included with DRAGEN since v3.5. The table below indicates which version of Annotations binaries were included with different DRAGEN releases, and their AI annotation capabilities.

The Annotations binaries distributed with DRAGEN can not be changed. Newer versions of Annotations are backward compatible, and can therefore annotate output files from older DRAGEN releases.

DRAGEN version(s)

Annotations version

AI annotations

Documentation

Data Utility

4.5

3.27.0

spliceAI, primateAI3D, PromoterAI

3.27

Data Manager

4.4

3.25.1