variation-normalizer 0.15.4

VICC normalization routine for variations

Variation Normalization

The Variation Normalizer parses and translates free-text descriptions of genomic variations into computable objects conforming to the Variation Representation Specification (VRS), enabling consistent and accurate variant harmonization across a diversity of genomic knowledge resources.

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Live OpenAPI endpoint

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Installation

Install from PyPI:

python3 -m pip install variation-normalizer

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variation-normalization branch	variation-normalizer version	gene-normalizer version	VRS version
main	>=0.14.Z	>=0.9.Z	2.0

About

Variation Normalization works by using four main steps: tokenization, classification, validation, and translation. During tokenization, we split strings on whitespace and parse to determine the type of token. During classification, we specify the order of tokens a classification can have. We then do validation checks such as ensuring references for a nucleotide or amino acid matches the expected value and validating a position exists on the given transcript. During translation, we return a VRS Allele object.

Variation Normalization is limited to the following types of variants:

• HGVS expressions and text representations (ex: BRAF V600E):
  • protein (p.): substitution, deletion, insertion, deletion-insertion
  • coding DNA (c.): substitution, deletion, insertion, deletion-insertion
  • genomic (g.): substitution, deletion, ambiguous deletion, insertion, deletion-insertion, duplication
• gnomAD-style VCF (chr-pos-ref-alt, ex: 7-140753336-A-T)
  • genomic (g.): substitution, deletion, insertion

Variation Normalizer accepts input from GRCh37 or GRCh8 assemblies.

We are working towards adding more types of variations, coordinates, and representations.

VRS Versioning

The variation-normalization repo depends on VRS models, and therefore each variation-normalizer package on PyPI uses a particular version of VRS. The correspondences between packages may be summarized as:

variation-normalization branch	variation-normalizer version	gene-normalizer version	VRS version
main	>=0.14.Z	>=0.9.Z	2.0

Previous VRS Versioning

The correspondences between the packages that are no longer maintained may be summarized as:

variation-normalization branch	variation-normalizer version	gene-normalizer version	VRS version
vrs-1.3	0.6.Z	0.1.Z	1.3

Available Endpoints

/to_vrs

Returns a list of validated VRS Variations.

/normalize

Returns a VRS Variation aligned to the prioritized transcript. The Variation Normalizer relies on Common Operations On Lots-of Sequences Tool (cool-seq-tool) for retrieving the prioritized transcript data. More information on the transcript selection algorithm can be found here.

If a genomic variation query is given a gene (E.g. BRAF g.140753336A>T), the associated cDNA representation will be returned. This is because the gene provides additional strand context. If a genomic variation query is not given a gene, the GRCh38 representation will be returned.

Development

Clone the repo:

git clone https://github.com/cancervariants/variation-normalization.git
cd variation-normalization

For a development install, we recommend using Pipenv. See the pipenv docs for direction on installing pipenv in your compute environment.

Once installed, from the project root dir, just run:

pipenv shell
pipenv update && pipenv install --dev

Required resources

Variation Normalization relies on some local data caches which you will need to set up. We provide instructions on how to setup your development environment using Docker.

• SeqRepo: You must setup SeqRepo locally following these steps.
• Gene Normalizer: The Variation Normalizer uses Gene Normalizer to get normalized gene concept information.
• Universal Transcript Archive (UTA): The Variation Normalizer uses Common Operations On Lots-of Sequences Tool (cool-seq-tool) which uses UTA as the underlying PostgreSQL database.

SeqRepo

Variation Normalization relies on seqrepo, which you must download yourself.

Variation Normalizer uses seqrepo to retrieve sequences at given positions on a transcript.

From the root directory:

pip install seqrepo
sudo mkdir /usr/local/share/seqrepo
sudo chown $USER /usr/local/share/seqrepo
seqrepo pull -i 2024-12-20/  # Replace with latest version using `seqrepo list-remote-instances` if outdated

If you get an error similar to the one below:

PermissionError: [Error 13] Permission denied: '/usr/local/share/seqrepo/2024-12-20/._fkuefgd' -> '/usr/local/share/seqrepo/2024-12-20/'

You will want to do the following:
(Might not be ._fkuefgd, so replace with your error message path)

sudo mv /usr/local/share/seqrepo/2024-12-20._fkuefgd /usr/local/share/seqrepo/2024-12-20
exit

Use the SEQREPO_ROOT_DIR environment variable to set the path of an already existing SeqRepo directory. The default is /usr/local/share/seqrepo/latest.

UTA

You must download uta_20241220.pgd.gz from https://dl.biocommons.org/uta/ using a web browser and move it to the root of the repository.

Docker Installation (Preferred)

We recommend installing the Variation Normalizer using Docker.

Requirements

• Docker

Build, (re)create, and start containers

docker volume create uta_vol
docker compose up

[!IMPORTANT] This assumes you have a local SeqRepo installed at /usr/local/share/seqrepo/2024-12-20. If you have it installed elsewhere, please update the SEQREPO_ROOT_DIR environment variable in compose.yaml.
If you're using Docker Desktop, you'll want to go to Settings -> Resources -> File sharing and add /usr/local/share/seqrepo under the Virtual file shares section. Otherwise, you will get the following error: OSError: Unable to open SeqRepo directory /usr/local/share/seqrepo/2024-12-20.

[!TIP] If you want a clean slate, run docker compose down -v to remove containers and volumes, then docker compose up --build to rebuild and start fresh containers.

Point your browser to http://localhost:8001/variation/.

Code QC

Code style is managed by Ruff and checked prior to commit.

To perform formatting and check style:

python3 -m ruff format . && python3 -m ruff check --fix .

We use pre-commit to run conformance tests.

This ensures:

• Style correctness
• No large files
• AWS credentials are present
• Private key is present

Pre-commit must be installed before your first commit. Use the following command:

pre-commit install

Testing

From the root directory of the repository:

pytest tests/