v3.18.1

Features

Issue key	Summary
NIR-1003	Update ClinGen Dosage Sensitivity Map
NIR-1002	Update ClinGen Gene Disease Validity
NIR-1001	Update dbSNP to v155
NIR-1000	Update OMIM to May 2022
NIR-999	Update ClinVar to May 2022
NIR-969	Add DECIPHER SVs to Nirvana
NIR-926	Remove Variant recomposition

Bugs Fixed

Issue key	Summary
NIR-1038	Nirvana displays confusing error message if idx files for gsa files are absent
NIR-1014	Downloader is not using new SA manifest architecture
NIR-996	Nirvana returns duplicate VCVs in ClinVar
NIR-976	Jasix crashes if range is out of the range in the file

Unresolved Bugs

Issue key	Summary
NIR-919	Nirvana does not handle protein sequences that are partially aligned to the genome
NIR-918	Nirvana does not handle ribosomal frameshifts properly during translation
NIR-917	Nirvana does not truncate deletions that start within a deletion RNA-edit (HGVS c.)
NIR-916	Nirvana does not detect HGVS c. duplications when inserting a base into a deletion RNA-edit
NIR-915	Nirvana does not convert SNVs that land in a deletion RNA-edit as an insertion (HGVS c.)
NIR-909	Nirvana Lambda throws Nirvana error if input VCF is not BGZipped
NIR-701	Nirvana should simplify HGVS p. notation for deletions that disrupt the initiation codon
NIR-702	Nirvana should stop after inserted terminal codon in HGVS p.
NIR-703	Nirvana incorrectly handles deletions across the terminal codon in HGVS p.
NIR-667	Nirvana is unable to count the # of AA until new stop codon (HGVS p. frameshift)
NIR-666	Nirvana creates frameshift HGVS p. notation when extension is expected
NIR-665	Nirvana uses incorrect HGVS p. notation for disrupted translation initiation codons
NIR-602	SAUtils CustomVar won't allow missing values for Score columns
NIR-504	SingleAnnotation behaves differently in Lambda vs REST API
NIR-220	Incorrect HGVS p. results because Nirvana does not use the transcript sequence
NIR-219	Nirvana reports incorrect HGVS p. for non-AUG start codon variants
NIR-215	Nirvana incorrectly determines gnomAD low complexity regions at translocation breakend boundaries
NIR-86	Nirvana incorrectly handles insertions where RNA-edit insertions already occur
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)

v3.18.0

Features

Issue key	Summary
NIR-987	Support Custom Sample Format fields
NIR-927	Update Nirvana to use net6.0
NIR-826	Update ClinGen gene disease validity to Feb 14, 2022 version
NIR-825	Update ClinGen dosage sensitivity to Feb 14, 2022 version
NIR-824	Update OMIM to Dec 02, 2021 version
NIR-823	Update ClinVar to Dec 2021
NIR-783	Support Custom INFO fields
NIR-779	Add support for DANN scores
NIR-778	Add support for GERP++ conservation scores
NIR-775	Add support for GME Variome
NIR-773	Add support for gnomAD 2.1 SV

Bugs Fixed

Issue key	Summary
NIR-975	Nirvana JSON uses inconsistent decimal identifiers
NIR-913	Nirvana lambda signature expires if Annotation lambda takes more than 5 mins
NIR-912	Nirvana missing triplosensitivity in annotation
NIR-874	GeneAnnotationLambda always uses 'latest' manifest
NIR-810	Custom Annotation should provide input line when an error is encountered
NIR-759	Nirvana lambda throws Nirvana error when signature expires
NIR-582	Jasix incorrectly closes the JSON header when combining query with header
NIR-479	Single Annotation lambda should handle incorrect alt alleles more robustly

Unresolved Bugs

Issue key	Summary
NIR-996	Nirvana returns duplicate VCVs in ClinVar
NIR-976	Jasix crashes if range is out of the range in the file
NIR-919	Nirvana does not handle protein sequences that are partially aligned to the genome
NIR-918	Nirvana does not handle ribosomal frameshifts properly during translation
NIR-917	Nirvana does not truncate deletions that start within a deletion RNA-edit (HGVS c.)
NIR-916	Nirvana does not detect HGVS c. duplications when inserting a base into a deletion RNA-edit
NIR-915	Nirvana does not convert SNVs that land in a deletion RNA-edit as an insertion (HGVS c.)
NIR-909	Nirvana Lambda throws Nirvana error if input VCF is not BGZipped
NIR-701	Nirvana should simplify HGVS p. notation for deletions that disrupt the initiation codon
NIR-702	Nirvana should stop after inserted terminal codon in HGVS p.
NIR-703	Nirvana incorrectly handles deletions across the terminal codon in HGVS p.
NIR-667	Nirvana is unable to count the # of AA until new stop codon (HGVS p. frameshift)
NIR-666	Nirvana creates frameshift HGVS p. notation when extension is expected
NIR-665	Nirvana uses incorrect HGVS p. notation for disrupted translation initiation codons
NIR-602	SAUtils CustomVar won't allow missing values for Score columns
NIR-504	SingleAnnotation behaves differently in Lambda vs REST API
NIR-220	Incorrect HGVS p. results because Nirvana does not use the transcript sequence
NIR-219	Nirvana reports incorrect HGVS p. for non-AUG start codon variants
NIR-215	Nirvana incorrectly determines gnomAD low complexity regions at translocation breakend boundaries
NIR-86	Nirvana incorrectly handles insertions where RNA-edit insertions already occur
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)

3.2.6

This is the latest release in our Nirvana 3.2.x branch series used by the TruSight Oncology team at Illumina. This release uses the latest and greatest transcripts and genes directly from RefSeq.

Running Nirvana

Nirvana 3.2.6 has some difference compared with Nirvana 3.2.5:

• the cache data now comes directly from RefSeq rather than from VEP. As such there are slight differences. For example, RefSeq uses official Sequence Ontology terms for the transcript biotypes rather than the related Ensembl terminology.
• Phantom variant recomposition has been disabled for the time being
• SIFT and PolyPhen are currently not available in the normal cache, but they are available for the transcripts in our CDx cache
• the Nirvana command-line now asks for a cache directory rather than a cache path prefix

A typical Nirvana 3.2.6 command-line might look like this:

dotnet bin/Nirvana.dll -i NA12878.vcf.gz -c Data/Cache/GRCh37 -r Data/References/Homo_sapiens.GRCh37.Nirvana.dat --sd Data/SupplementaryAnnotation/GRCh37 -o NA12878

Installation

Download the files

mkdir Nirvana-3.2.6
cd Nirvana-3.2.6
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/Reference-GRCh37.zip
wget https://github.com/Illumina/Nirvana/releases/download/v3.2.6/Nirvana-3.2.6-dotnet-6.0.zip
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/Cache-GRCh37-RefSeq.zip
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/Cache-GRCh37-CDx.zip
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/Cache-HGNC-GeneSymbols.zip
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/Cache-TSO500-GeneSymbols.zip
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/Sift-CDx-VEP91.zip
wget https://nirvana-prerelease.s3.us-west-2.amazonaws.com/PolyPhen-CDx-VEP91.zip

Unpack Nirvana

mkdir -p bin Data/Cache/GRCh37 Data/References Data/SupplementaryAnnotation/GRCh37
cd bin
unzip ../Nirvana-3.2.6-dotnet-6.0.zip

Unpack the data files

cd ../Data/Cache/GRCh37
unzip ../../../Cache-GRCh37-RefSeq.zip
unzip ../../../Cache-GRCh37-CDx.zip
unzip ../../../Cache-TSO500-GeneSymbols.zip
cd ../../References
unzip ../../Reference-GRCh37.zip
cd ../SupplementaryAnnotation/GRCh37
unzip ../../../Sift-CDx-VEP91.zip
unzip ../../../PolyPhen-CDx-VEP91.zip
cd ../../..

In the example above, we're unpacking the gene symbols (Cache-TSO500-GeneSymbols.zip) that were used in Nirvana 3.2.5. If you want the latest gene symbols from HGNC as of 2022-02-21, unpack the Cache-HGNC-GeneSymbols.zip file instead.

Checking the installation

dotnet bin/Nirvana.dll

You should see the following:

---------------------------------------------------------------------------
Nirvana                                             (c) 2022 Illumina, Inc.
Stromberg, Roy, Siddiqui, Platzer, et al.                             3.2.6
---------------------------------------------------------------------------

USAGE: dotnet Nirvana.dll -i <vcf path> -c <cache dir> --sd <sa dir> -r <ref path> -o <base output filename>
Annotates a set of variants

OPTIONS:
      --cache, -c <dir>      input cache dir
      --in, -i <path>        input VCF path
      --gvcf                 enables genome vcf output
      --vcf                  enables vcf output
      --out, -o <file path>  output file path
      --ref, -r <path>       input compressed reference sequence path
      --sd <directory>       input supplementary annotation directory
      --force-mt             forces to annotate mitochondrial variants
      --help, -h             displays the help menu
      --version, -v          displays the version

Cache version: 1, Supplementary annotation version: 50, Reference version: 7

If this doesn't work, you might need to install either the .NET 6.0 runtime or the .NET 6.0 SDK. However, if you're only running Nirvana, you only need the runtime.

Features

Issue key	Summary
NIR-920	Add support for MT transcripts
NIR-879	Add gene symbol override to Nirvana
NIR-876	Add support for discovering amino acid edits (non-canonical start codons, etc.)
NIR-872	Add support for RefSeq regulatory regions
NIR-798	Add support for multiple caches belonging to the same genome assembly
NIR-438	Create RefSeq Cache v28 files

Bugs fixed

Issue key	Summary
NIR-1036	Resolve consequence issues that were identified in VEP 105 comparison
NIR-703	Nirvana incorrectly handles deletions across the terminal codon in HGVS p.
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)

Unresolved bugs

Issue key	Summary	Fix Version
NIR-919	Nirvana does not handle protein sequences that are partially aligned to the genome
NIR-918	Nirvana does not handle ribosomal frameshifts properly during translation
NIR-721	Nirvana does not properly preload <NON_REF> variants	3.9.0
NIR-714	Nirvana should trim and LS variants during TopMed lift-over using dbSNP IDs	3.9.0
NIR-719	Nirvana does not remove missing values in 1KG SV IDs	3.8.0
NIR-722	Nirvana does not throw error when annotating unsorted VCF file	3.6.0
NIR-718	Nirvana reports zero allele frequencies for 1KG SV supplementary annotations	3.6.0
NIR-717	Nirvana does not annotate properly when variants fall into transcript gaps	3.5.0
NIR-713	Nirvana cannot handle OMIM phenotype 617956 (β-glucopyranoside tasting)	3.5.0
NIR-720	Nirvana creates empty custom annotations	3.3.0
NIR-716	Nirvana should assign copy_number_loss to <DEL> with SVTYPE=CNV	3.3.0
NIR-715	Nirvana provides extra PhyloP scores for some genomic positions	3.3.0
NIR-712	Nirvana is missing dbSNP annotations for mitochondrial variants	3.3.0
NIR-701	Nirvana should simplify HGVS p. notation for deletions that disrupt the initiation codon
NIR-86	Nirvana should use the transcript sequence for HGVS c. instead of reference

3.17

Features

Issue key	Summary
NIR-678	Update OMIM to the August 2021 version
NIR-674	Update ClinVar to the August 2021 version
NIR-671	Optimize memory for JSON outputs

Bugs fixed

Issue key	Summary
NIR-724	Buffer overrun in BgzipTextWriter
NIR-663	Nirvana λ is unable to handle empty VCF files
NIR-549	JWT validator doesn't work for api regions
NIR-212	Annotation lambdas run out of disk space when large amounts of CA are submitted

Unresolved bugs

Issue key	Summary
NIR-759	Nirvana lambda throws Nirvana error when signature expires
NIR-703	Nirvana incorrectly handles deletions across the terminal codon in HGVS p.
NIR-702	Nirvana should stop after inserted terminal codon in HGVS p.
NIR-701	Nirvana should simplify HGVS p. notation for deletions that disrupt the initiation codon
NIR-667	Nirvana is unable to count the # of AA until new stop codon (HGVS p. frameshift)
NIR-666	Nirvana creates frameshift HGVS p. notation when extension is expected
NIR-665	Nirvana uses incorrect HGVS p. notation for disrupted translation initiation codons
NIR-602	SAUtils CustomVar won't allow missing values for Score columns
NIR-582	Jasix incorrectly closes the JSON header when combining query with header
NIR-504	SingleAnnotation behaves differently in Lambda vs REST API
NIR-479	Single Annotation lambda should handle incorrect alt alleles more robustly
NIR-220	Incorrect HGVS p. results because Nirvana does not use the transcript sequence
NIR-219	Nirvana reports incorrect HGVS p. for non-AUG start codon variants
NIR-215	Nirvana incorrectly determines gnomAD low complexity regions at translocation breakend boundaries
NIR-86	Nirvana incorrectly handles insertions where RNA-edit insertions already occur
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)

3.2.5.1

Features

Issue key	Summary
NIR-636	Fix transcripts with translational readthrough (AA difference)
NIR-631	Add support for non-AUG start codons
NIR-627	Fix transcripts with cDNA frameshifts
NIR-625	Fix transcripts with cDNA substitutions
NIR-624	Fix transcripts with missing poly A tails in cDNA
NIR-456	Remove reference bases from HGVS notation

Bugs fixed

Issue key	Summary
NIR-702	Nirvana should stop after inserted terminal codon in HGVS p.
NIR-667	Nirvana is unable to count the # of AA until new stop codon (HGVS p. frameshift)
NIR-666	Nirvana creates frameshift HGVS p. notation when extension is expected
NIR-665	Nirvana uses incorrect HGVS p. notation for disrupted translation initiation codons
NIR-484	Incorrect gene models were found for NM_022148.2
NIR-220	Incorrect HGVS p. results because Nirvana does not use the transcript sequence
NIR-219	Nirvana reports incorrect HGVS p. for non-AUG start codon variants
NIR-57	Nirvana produces bizarre HGVS p. notation (NP_001137434.1:p.(Val701_?_fsTer?))
NIR-55	Nirvana produces invalid CDS positions

Unresolved bugs

Issue key	Summary	Fix Version
NIR-721	Nirvana does not properly preload <NON_REF> variants	3.9.0
NIR-714	Nirvana should trim and LS variants during TopMed lift-over using dbSNP IDs	3.9.0
NIR-719	Nirvana does not remove missing values in 1KG SV IDs	3.8.0
NIR-722	Nirvana does not throw error when annotating unsorted VCF file	3.6.0
NIR-718	Nirvana reports zero allele frequencies for 1KG SV supplementary annotations	3.6.0
NIR-717	Nirvana does not annotate properly when variants fall into transcript gaps	3.5.0
NIR-713	Nirvana cannot handle OMIM phenotype 617956 (β-glucopyranoside tasting)	3.5.0
NIR-720	Nirvana creates empty custom annotations	3.3.0
NIR-716	Nirvana should assign copy_number_loss to <DEL> with SVTYPE=CNV	3.3.0
NIR-715	Nirvana provides extra PhyloP scores for some genomic positions	3.3.0
NIR-712	Nirvana is missing dbSNP annotations for mitochondrial variants	3.3.0
NIR-703	Nirvana incorrectly handles deletions across the terminal codon in HGVS p.
NIR-701	Nirvana should simplify HGVS p. notation for deletions that disrupt the initiation codon
NIR-86	Nirvana should use the transcript sequence for HGVS c. instead of reference
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)

3.16.1

Features

Issue key	Summary
NIR-630	Increased gzip compression level
NIR-651	Renamed TCGA & TumorFusions data sources

Bugs fixed

Unresolved bugs

Issue key	Summary
NIR-602	SAUtils CustomVar won't allow missing values for Score columns
NIR-582	Jasix incorrectly closes the JSON header when combining query with header
NIR-504	SingleAnnotation behaves differently in Lambda vs REST API
NIR-220	Nirvana doesn't use the transcript sequence to report the reference amino acids in HGVS p. notations
NIR-219	Nirvana reports ambiguous protein level annotations for CUG start codon variants
NIR-218	Duplicates may be marked as insertions in HGVS
NIR-217	Nirvana produces HGVS insertions notations that are more than one bp apart
NIR-215	Nirvana incorrectly determines gnomAD low complexity regions at translocation breakend boundaries
NIR-212	Annotation lambdas run out of disk space when large amounts of CA are submitted
NIR-91	Nirvana should fully right align duplications in HGVS c. notation
NIR-87	Nirvana should detect duplications in HGVS by looking at the transcript sequence.
NIR-86	Nirvana incorrectly handles insertions where RNA-edit insertions already occur
NIR-75	Nirvana doesn't handle 3' UTR intron HGVS c. notation properly
NIR-57	Nirvana produces bizarre HGVS p. notation (NP_001137434.1:p.(Val701_?_fsTer?))
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)
NIR-55	Nirvana produces a strange CDS position range for NM_001346067.1

3.15

Features

Issue key	Summary
NIR-574	Update OMIM
NIR-569	Update ClinVar
NIR-540	Add command-line arguments to the Downloader for changing S3 URLs and manifest filenames
NIR-520	Add support for identifying in-frame gene fusions
NIR-495	Port bidirectional allele trimmer fix for breakend locations when using legacy VID mode
NIR-494	Port legacy VID fixes from 3.6.x
NIR-480	Add support for INV3/INV5 tags with respect to gene fusions
NIR-477	Add support for FusionCatcher data sources
NIR-474	Add support for COSMIC gene fusions
NIR-459	Update HGVS g. notation for MT variants to use m. notation
NIR-324	Allow masked reference bases in PAR regions (chrY)
NIR-257	Update Nirvana to use gnomAD 3.1 for GRCh38
NIR-250	Update the BlockCompression library
NIR-193	Add support for detecting out of disk space issues in Downloader

Bugs fixed

Issue key	Summary
NIR-548	Nirvana incorrectly recomposes an deletion and assigns a negative genotype
NIR-398	Mito Heteroplasmy not using trimmed and left-aligned alt alleles for annotation
NIR-214	Nirvana doesn't support regular gzip VCF file
NIR-213	Downloader unintentionally removes genomic reference file

Unresolved bugs

Issue key	Summary
NIR-602	SAUtils CustomVar won't allow missing values for Score columns
NIR-582	Jasix incorrectly closes the JSON header when combining query with header
NIR-504	SingleAnnotation behaves differently in Lambda vs REST API
NIR-220	Nirvana doesn't use the transcript sequence to report the reference amino acids in HGVS p. notations
NIR-219	Nirvana reports ambiguous protein level annotations for CUG start codon variants
NIR-218	Duplicates may be marked as insertions in HGVS
NIR-217	Nirvana produces HGVS insertions notations that are more than one bp apart
NIR-215	Nirvana incorrectly determines gnomAD low complexity regions at translocation breakend boundaries
NIR-212	Annotation lambdas run out of disk space when large amounts of CA are submitted
NIR-91	Nirvana should fully right align duplications in HGVS c. notation
NIR-87	Nirvana should detect duplications in HGVS by looking at the transcript sequence.
NIR-86	Nirvana incorrectly handles insertions where RNA-edit insertions already occur
NIR-75	Nirvana doesn't handle 3' UTR intron HGVS c. notation properly
NIR-57	Nirvana produces bizarre HGVS p. notation (NP_001137434.1:p.(Val701_?_fsTer?))
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)
NIR-55	Nirvana produces a strange CDS position range for NM_001346067.1

3.14

Features

Issue key	Summary
NIR-210	Cap VRF to 0.999

Bugs fixed

Unresolved bugs

Issue key	Summary
NIR-220	Nirvana doesn't use the transcript sequence to report the reference amino acids in HGVS p. notations
NIR-219	Nirvana reports ambiguous protein level annotations for CUG start codon variants
NIR-218	Duplicates may be marked as insertions in HGVS
NIR-217	Nirvana produces HGVS insertions notations that are more than one bp apart
NIR-216	Nirvana reports extra ClinVar SNVs where there is no alternate allele in XML source file
NIR-215	Nirvana incorrectly determines gnomAD low complexity regions at translocation breakend boundaries
NIR-214	Nirvana doesn't support regular gzip VCF file
NIR-213	Downloader unintentionally removes genomic reference file
NIR-212	Annotation lambdas run out of disk space when large amounts of CA are submitted
NIR-91	Nirvana should fully right align duplications in HGVS c. notation
NIR-87	Nirvana should detect duplications in HGVS by looking at the transcript sequence.
NIR-86	Nirvana incorrectly handles insertions where RNA-edit insertions already occur
NIR-75	Nirvana doesn't handle 3' UTR intron HGVS c. notation properly
NIR-57	Nirvana produces bizarre HGVS p. notation (NP_001137434.1:p.(Val701_?_fsTer?))
NIR-56	CDS position goes beyond the CDS sequence length (NM_001300952.1)
NIR-55	Nirvana produces a strange CDS position range for NM_001346067.1

3.13

• Major increase in annotation accuracy for RefSeq transcripts. 59% reduction in HGVS issues.
• Better support for reference variants when producing HGVS g. notation

3.12

• Updated ClinVar & OMIM
• Improved error handling when using the gene custom annotation files
• Added support for gnomAD 3.0 (but not active due to file size limitations in our CDN)
• Added support for handling custom annotation genomic regions that also include symbolic alleles