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CircleCI pypi

Predict splicing variant effect from VCF

Paper: Cheng et al.


Usage example

pip install mmsplice


1. Prepare annotation (gtf) file

Standard human gene annotation file in GTF format can be downloaded from ensembl or gencode. MMSplice can work directly with those files, however, some filtering is higly recommended.

  • Filter for protein coding genes.
  • Filter out duplicated exons. The same exon can be annotated multiple times if it appears in multiple transcripts. This will cause duplicated predictions.

We provide a filtered version here. Note this version has chromosome names in the format chr*. You may need to remove them to match the chromosome names in your fasta file.

2. Prepare variant (VCF) file

A correctly formatted VCF file with work with MMSplice, however the following steps will make it less prone to false positives:

  • Quality filtering. Low quality variants leads to unreliable predictions.
  • Avoid presenting multiple variants in one line by splitting them into multiple lines. Example code to do it:
    bcftools norm -m-both -o out.vcf in.vcf.gz
  • Left-normalization. For instance, GGCA-->GG is not left-normalized while GCA-->G is. Details for unified representation of genetic variants see Tan et al.
    bcftools norm -f reference.fasta -o out.vcf in.vcf

3. Prepare reference genome (fasta) file

Human reference fasta file can be downloaded from ensembl/gencode. Make sure the chromosome name matches with GTF annotation file you use.

Example code

Check notebooks/example.ipynb

To score variants (including indels), we suggest to use primarily the deltaLogitPSI predictions, which is the default output. The differential splicing efficiency (dse) model was trained from MMSplice modules and exonic variants from MaPSy, thus only the predictions for exonic variants are calibrated.

# Import
from mmsplice.vcf_dataloader import SplicingVCFDataloader
from mmsplice import MMSplice, predict_all_table
from mmsplice.utils import max_varEff

# example files
gtf = 'tests/data/test.gtf'
vcf = 'tests/data/test.vcf.gz'
fasta = 'tests/data/hg19.nochr.chr17.fa'
gtfIntervalTree = 'tests/data/test.pkl' # pickle exon interval Tree

# dataloader to load variants from vcf
dl = SplicingVCFDataloader(gtf,
                          out_file=gtfIntervalTree, # same pikled gtf IntervalTree

# Specify model
model = MMSplice(

 # Do prediction
 predictions = predict_all_table(model, dl, batch_size=1024, split_seq=False, assembly=False)

 # Summerize with maximum effect size
 predictionsMax = max_varEff(predictions)

VEP Plugin

The VEP plugin wraps the prediction function from mmsplice python package. Please check documentation of vep plugin under VEP_plugin/

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