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Variant Effect Predictor Download and install


Download

Download ensembl-vep package (see below the different ways to download it) and then follow the installation instructions.


Using Git

Clone the Git repository

Use git to download the ensembl-vep package:

git clone https://github.com/Ensembl/ensembl-vep.git
cd ensembl-vep

Update to a newer version

To update from a previous version:

cd ensembl-vep
git pull
git checkout release/98
perl INSTALL.pl

Use an older version

To use an older version (this example shows how to set up release 87):

cd ensembl-vep
git checkout release/87
perl INSTALL.pl

Download the Zipped package file

Users without the git utility installed may download a zip file from GitHub, though we would always recommend using git if possible.

curl -L -O https://github.com/Ensembl/ensembl-vep/archive/release/98.zip
unzip 98.zip
cd ensembl-vep-release-98/

Previous versions (ensembl-tools)

Previously VEP was available as part of the ensembl-tools package (see the Ensembl archive site for documentation). The following downloads are available for archival purposes. Show versions


What's new

New in version 98 (September 2019)

  • Human GRCh38 cache files now contain variants from dbSNP152
  • This employs a new clustering strategy which may result in different rsIDs being reported as known variants for some insertions and deletions - for more information see here
  • --clin_sig_allele has been updated to be used by default
  • New options:
    • --custom_multi_allelic: prevents VEP from assuming that comma separated lists in custom annotations are allele specific
  • MANE attributes are now included within VEP cache files, web VEP and REST
  • VEP plugins:
    • satMutMPRA - new: measures variant effects on gene RNA expression for 21 regulatory elements
  • VEP Installer:
    • HTSLib v1.9 is now installed by default (previously v1.3.2)
    • Bio::DB::HTS v2.11 is now installed by default (previously v2.9)
    • New option 'PLUGINSDIR' allows you to specify the installation directory for plugins

Previous version history - from version 88: Show

Older versions (ensembl-tools) - until version 87: Show


Requirements

VEP requires:
  • gcc, g++ and make
  • Perl version 5.10 or above recommended (tested on 5.10, 5.14, 5.18, 5.22, 5.26)
  • Perl packages: See this guide for more information on how to install perl modules.
    Additional libraries can be installed for extra features and enhancements but they are not required to run VEP in most of the use cases.

VEP's INSTALL.pl script will install required components of Ensembl API for you, but VEP may also be used with any pre-existing API installations you have, provided their versions match the version of VEP you are using.

VEP has been developed for UNIX-like environments and works well on Linux (e.g. Ubuntu, Debian, Mint) and Mac OSX.
It can also be used on Windows systems with a more involved installation process.


Installation

VEP's INSTALL.pl makes it easy to set up your environment for using the VEP. It will download and configure a minimal set of the Ensembl API for use by the VEP, and can also download cache files, FASTA files and plugins.

Run the following, and follow any prompts as they appear:

perl INSTALL.pl

Additional non-essential components and enhancements must be installed manually.


Software components installed

If you already have the latest version of the API installed you do not need to run the installer, although it can be used to simply update your API version (with post-release patches applied), and retrieve cache and FASTA files. The installer downloads the API within the VEP directory and will not affect any other Ensembl API installations.

The script will also attempt to install a Perl::XS module, Bio::DB::HTS, for rapid access to bgzipped FASTA files. If this fails, you may add the --NO_HTSLIB flag when running the installer; VEP will fall back to using Bio::DB::Fasta for this functionality (more details).


Running the installer

The installer is run on the command line as follows:

 perl INSTALL.pl [options] 

Follow on-screen prompts and note warnings of any files which will be deleted/overwritten

You should not need to add any options, but configuration of the installer is possible with the following flags:

Flag Alternate Description
--ASSEMBLY
-y
Assembly version to use when using --AUTO. Most species have only one assembly available on each software release; currently this is only required for human on release 76 onwards.
--AUTO
-a
Run installer without prompts. Use the following options to specify parts to install:
  • a (API + Bio::DB::HTS/htslib)
  • l (Bio::DB::HTS/htslib only)
  • c (cache)
  • f (FASTA)
  • p (plugins) — Require the use of the --PLUGINS flag to list the plugin(s) to install.

e.g. for API and cache:

perl INSTALL.pl --AUTO ac
--CACHE_VERSION [version]
  By default the installer will download the latest version of VEP caches and FASTA files (currently 98). You can force the script to install a different version, but there is no guarantee that a version of the API will be compatible with a different version of the cache.
--CACHEDIR [dir]
-c

By default the script will install the cache files in the ".vep" subdirectory in your home area. This option configures where cache files are installed.

The --dir_cache flag must be passed when running the VEP if a non-default cache directory is given:

./vep --dir_cache [dir]
--DESTDIR [dir]
-d

By default the script will install the API modules in a subdirectory of the current directory named "Bio". Using this option you can configure where the Bio directory is created. If something other than the default is used, this directory must either be added to your PERL5LIB environment variable when running the VEP, or included using perl's -I flag:

perl -I [dir] vep
--NO_HTSLIB
-l
Don't attempt to install Bio::DB::HTS/htslib
--NO_TEST
  Don't run API tests - useful if you know a harmless failure will prevent continuation of the installer
--NO_UPDATE
-n
By default the script will check for new versions or updates of the VEP. Using this option will skip this check.
--PLUGINS
-g

Comma-separated list of plugins to install when using --AUTO. To install all available plugins, use --PLUGINS all.

# List the available plugins:
perl INSTALL.pl -a p --PLUGINS list
# Download/install all the available plugins:
perl INSTALL.pl -a p --PLUGINS all
# Download/install a defined list of plugins, e.g.:
perl INSTALL.pl -a p --PLUGINS dbNSFP,CADD,G2P
--PLUGINSDIR [dir]
-r

By default the script will install the plugins files in the "Plugins" subdirectory of the --CACHEDIR directory. This option configures where the plugins files are installed.

The --dir_plugins flag must be passed when running the VEP if a non-default plugins directory is given:

./vep --dir_plugins [dir]
--PREFER_BIN
-p
Use this if the installer fails with out of memory errors.
--SPECIES
-s
Comma-separated list of species to install when using --AUTO. To install the RefSeq cache, add "_refseq" to the species name, e.g. "homo_sapiens_refseq", or "_merged" to install the merged Ensembl/RefSeq cache. Remember to use --refseq or --merged when running the VEP with the relevant cache!
--QUIET
-q
Don't write any status output when using --AUTO.

Additional components

INSTALL.pl will set up the minimum requirements for VEP. Some features and enhancements, however, require the installation of additional components. Most are perl modules that are easily installed using cpanm; see this guide for more information on how to install perl modules.

Typically, you will use cpanm to install modules locally in your home directories; this shows how to set up a path for perl modules and install one there:

mkdir -p $HOME/cpanm
export PERL5LIB=$PERL5LIB:$HOME/cpanm/lib/perl5
cpanm -l $HOME/cpanm Set::IntervalTree

To make the change to PERL5LIB permanent, it is recommended to add the export line to your $HOME/.bashrc or $HOME/.profile.


Bio::DB::BigFile

In order for VEP to be able to access bigWig format custom annotation files, the Bio::DB::BigFile perl module is required. Installation involves downloading and compiling the kent source tree. The current version of the kent source tree does not work correctly with Bio::DB::BigFile, so it is necessary to install an archive version known to work (v335).

  1. Download and unpack the kent source tree

    wget https://github.com/ucscGenomeBrowser/kent/archive/v335_base.tar.gz
    tar xzf v335_base.tar.gz
  2. Set up some environment variables; these are required only temporarily for this installation process

    export KENT_SRC=$PWD/kent-335_base/src
    export MACHTYPE=$(uname -m)
    export CFLAGS="-fPIC"
    export MYSQLINC=`mysql_config --include | sed -e 's/^-I//g'`
    export MYSQLLIBS=`mysql_config --libs`
  3. Modify kent build parameters

    cd $KENT_SRC/lib
    echo 'CFLAGS="-fPIC"' > ../inc/localEnvironment.mk
  4. Build kent source

    make clean && make
    cd ../jkOwnLib
    make clean && make

    If either of these steps fail, you may have some missing dependencies. Known common missing dependencies are libpng and libssl; these may be installed, for example, with apt-get on Ubuntu. If you do not have sudo access you may have to ask your sysadmin to install any missing dependencies.

    sudo apt-get install libpng-dev libssl-dev

    On Mac OSX you may use brew; the openssl libraries also need to be symbolically linked to a different path:

    brew install libpng openssl
    cd /usr/local/include
    ln -s ../opt/openssl/include/openssl .
    cd -
  5. On some systems (e.g. Mac OSX), a compiled file is placed in a path that Bio::DB::BigFile cannot find. You can correct this with:

    ln -s $KENT_SRC/lib/x86_64/* $KENT_SRC/lib/
  6. We'll now use cpanm to install the perl module for Bio::DB::BigFile itself. See above for guidance on this. In this example we're going to install the module to a path within your home directory. In order to do this we must modify the paths that perl looks in to find modules by adding to the PERL5LIB environment module. To make this change permanent you must add the export line to your $HOME/.bashrc or $HOME/.profile.

    mkdir -p $HOME/cpanm
    export PERL5LIB=$PERL5LIB:$HOME/cpanm/lib/perl5
    cpanm -l $HOME/cpanm Bio::DB::BigFile

    If you are prompted for the path to the kent source tree, that means something didn't go right in the compilation above. Double check that $KENT_SRC/lib/jkweb.a exists and is not found instead at e.g. $KENT_SRC/lib/x86_64/jkweb.a. You may copy or link the file (and the other files in that directory) to the former path.

    ln -s $KENT_SRC/lib/x86_64/* $KENT_SRC/lib/
  7. You should now be able to successfully run the appropriate test in the VEP package:

    perl -Imodules t/AnnotationSource_File_BigWig.t

Using VEP in Mac OS

Installing VEP on Mac OS is slightly trickier than other Linux-based systems, and will require additional dependancies.
These instructions will guide you through the setup of Perlbrew, Homebrew, MySQL and other dependancies that will allow for a clean installation of VEP on your Mac OS system.

These instructions have been tested on macOS High Sierra (10.13) and macOS Sierra (10.12).
Older versions may require additional tweaks, however we shall endeavor to keep these instructions up to date for future versions of MacOS.


Prerequisite Setup

List of prerequisites: XCode, GCC, Perlbrew, Cpanm, Homebrew, mysql, DBI, DBD::mysql

XCode and GCC

VEP requires XCode and GCC for installation purposes. Fortunately, recent versions of macOS will look for (and attempt to install if required) both of these when you run the following command:

gcc -v

Perlbrew

We recommend using Perlbrew to install a new version of Perl on your mac, to prevent messing with the vendor perl too much. This can be done with the following command:

curl -L http://install.perlbrew.pl | bash

echo 'source $HOME/perl5/perlbrew/etc/bashrc' >> ~/.bash_profile

At this point, PLEASE RESTART YOUR TERMINAL WINDOW to allow for the perlbrew changes to take effect.

We recommend installing Perl version 5.26.2 to run VEP, and installing cpanm to handle the installation of perl modules.
These steps can be completed with the commands:

perlbrew install -j 5 --as 5.26.2 --thread --64all -Duseshrplib perl-5.26.2 --notest
perlbrew switch 5.26.2
perlbrew install-cpanm

Homebrew

This package management system for Mac OS would make the installation of the next prerequisite (i.e. xs) easier.

/usr/bin/ruby -e "$(curl -fsSL https://raw.githubusercontent.com/Homebrew/install/master/install)"

xz

VEP requires the installation of xz, a data-compression utility. The easiest way to install the xz package is through homebrew:

brew install xz

MySQL

In order to connect to the Ensembl databases, a collection of MySQL related dependancies are required. Fortunately, these can be installed neatly with Homebrew and Cpanm:

brew install mysql
cpanm DBI
cpanm DBD::mysql

Installing BioPerl

On some versions of macOS, the VEP installer fails to cleanly install BioPerl, so a manual install will prevent issues:

curl -O https://cpan.metacpan.org/authors/id/C/CJ/CJFIELDS/BioPerl-1.6.924.tar.gz
tar zxvf BioPerl-1.6.924.tar.gz
echo 'export PERL5LIB=${PERL5LIB}:##PATH_TO##/bioperl-1.6.924' >> ~/.bash_profile

where ##PATH_TO##/bioperl-1.6.924 refers to the location of the newly unzipped BioPerl directory.


Final Dependancies

Installing the following Perl modules with cpanm will allow for full VEP functionality:

cpanm Test::Differences Test::Exception Test::Perl::Critic Archive::Zip PadWalker Error Devel::Cycle Role::Tiny::With Module::Build

export DYLD_LIBRARY_PATH=/usr/local/mysql/lib/:$DYLD_LIBRARY_PATH

Installing VEP

And that should be that! You should now be able to install VEP using the installer:

git clone https://github.com/ensembl/ensembl-vep
cd ensembl-vep
perl INSTALL.pl --NO_TEST

Using VEP in Windows

VEP was developed as a command-line tool, and as a Perl script its natural environment is a Linux system. However, there are several ways you can use VEP on a Windows machine.

You may also consider using VEP's web or REST interfaces.


Virtual machines

Using a virtual machine you can run a virtual Linux system in a window on your machine. There are two ways to do this:

  1. Use the Ensembl virtual machine image
  2. Use Docker

DWIMperl

DWIMperl has a Windows package that contains base requirements for setting up VEP.

  1. Download and install DWIMperl for Windows
  2. Download and unpack the zip of the ensembl-vep package
  3. Open a Command Prompt (search for Command Prompt in the Start Menu)
  4. Navigate to the directory where you unpacked the VEP package, e.g.

    cd Downloads/ensembl-vep-release-98
  5. Run INSTALL.pl with --NO_HTSLIB and --NO_TEST; you will see some warnings about the "which" command not being available (these will also appear when running VEP and can be ignored).

    perl INSTALL.pl --NO_HTSLIB --NO_TEST

Docker

Docker allows you to run applications in virtualised "containers". A docker image for VEP is available from DockerHub: VEP in DockerHub

The VEP Docker image uses ubuntu:18.04 as base image.

Commands to download the VEP Docker image (need to download and install the docker client beforehand):

docker pull ensemblorg/ensembl-vep
docker run -t -i ensemblorg/ensembl-vep ./vep

Currently no volumes are pre-configured for the container; this is required if you wish to download data (e.g. cache files) that persists across sessions.

The following is a brief example showing how to use a directory on your local (host) machine to store cache data for VEP.

# Create a directory on your machine:
mkdir $HOME/vep_data

# Make sure that the created directory on your machine has read and write access granted
# so the docker container can write in the directory (VEP output):
chmod a+rwx $HOME/vep_data    

docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep

Note

The Ensembl VEP API and all the required components (e.g. other Perl APIs, Bio::DB::HTS, htslib, ...) are already installed in the Docker image. That means you don't need to run the full INSTALL.pl.
However you can run the INSTALL.pl script with the options -a cfp to install the Cache data files, Fasta file and Plugins.
For more information, see the next section below.



Cache and Plugins installation

You will now be prompted by the installer if you wish to re-install the API. Type "n" followed by enter to skip to cache installation. You will be presented with a list of species; type the number for your species/assembly of interest and press enter. Your data will now download and unpack; this may take a while.

If you wish to retrieve HGVS annotations it is recommended to also download the FASTA file for your species. To do this, at the next prompt type "0" and press enter. You may skip the plugin installation also.

The above process may also be performed in one command; for example, to set up the cache and corresponding FASTA for human GRCh38:

docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep perl INSTALL.pl -a cf -s homo_sapiens -y GRCh38

If you wish to include the VEP plugins, add the 'p' value to the -a flag and the --PLUGINS (or -g) flag as well:

# Install all the available plugins:
docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep perl INSTALL.pl -a cfp -s homo_sapiens -y GRCh38 -g all
# or install a defined list of plugins:
docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep perl INSTALL.pl -a cfp -s homo_sapiens -y GRCh38 -g dbNSFP,CADD,G2P

The installer has now downloaded this data to $HOME/vep_data (and $HOME/vep_data/Plugins for the VEP plugins). VEP will automatically detect caches downloaded in this folder as it is mapped to VEP's default directory within the Docker instance.

docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep
./vep -i examples/homo_sapiens_GRCh38.vcf --cache

Read/Write access from the Docker container

In some distributions (e.g. CentOS, Fedora, Red Hat Enterprise Linux) Docker daemon requires root privileges (i.e. needs to prefix the command with sudo), which might cause read/write issues to the mounted volume.

One solution is to use the option :Z within the Docker -v option (only from docker 1.7.0):

sudo docker run -t -i -v $HOME/vep_data:/opt/vep/.vep:Z ensemblorg/ensembl-vep

An other solution is to change the read/write access of the mounted volume ($HOME/vep_data):

chmod -R a+rwx $HOME/vep_data



Mounted volume - recommended data structure

i.e. VEP data structure outside the Docker container


Diagram representing a recommended data file structure for the mounted volume

Here is an example of how you can run VEP using the setup presented in the image above (providing that the cache, the dbNSFP plugin and its data file have been downloaded):

docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep

# Example of VEP command line:
./vep --cache --offline --format vcf --vcf --force_overwrite \
--dir_cache /opt/vep/.vep/ \
--dir_plugins /opt/vep/.vep/Plugins/ \
--input_file /opt/vep/.vep/input/my_input.vcf \
--output_file /opt/vep/.vep/output/my_output.vcf \
--custom /opt/vep/.vep/custom/my_extra_data.bed,BED_DATA,bed,exact,1 \
--plugin dbNSFP,/opt/vep/.vep/Plugins/dbNSFP.gz,ALL

Note

The "Cache" and Plugins directories can be created and populated during the VEP installation process, using the flag -a (or --AUTO) with the parameters c (cache), f (fasta) and p (plugins).

e.g. for Human GRCh38:

docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep perl INSTALL.pl -a cfp -s homo_sapiens -y GRCh38


Update from a previous version

  1. Update your docker container

    # List containers
    docker ps -a
    # e.g.
    CONTAINER ID     IMAGE                        COMMAND          CREATED              STATUS                         PORTS          NAMES
    d64055ffe9e9     ensemblorg/ensembl-vep       "/bin/bash"      About a minute ago   Exited (0) 59 seconds ago                     tender_ritchie
    
    # Stop and remove old container
    docker stop tender_ritchie
    docker rm tender_ritchie
    
    # Update the container
    docker pull ensemblorg/ensembl-vep
  2. Update your cache

    # Install the new cache through the VEP INSTALL.pl script (see "Cache installation" section above)
    docker run -t -i -v $HOME/vep_data:/opt/vep/.vep ensemblorg/ensembl-vep perl INSTALL.pl -a c
    
    # Or you can install the cache manually
    cd $HOME/vep_data
    curl -O ftp://ftp.ensembl.org/pub/release-98/variation/vep/homo_sapiens_vep_98_GRCh38.tar.gz
    tar xzf homo_sapiens_vep_98_GRCh38.tar.gz