Ensembl’s Variant Effect Predictor is described in McLaren et al. (2016).
Prior to Bioconductor 3.19, the ensemblVEP package provided access to Ensembl’s predictions through an interface between Perl and MySQL.
In 3.19 VariantAnnotation supports the use of the VEP component of the REST API at https://rest.ensembl.org.
The function vep_by_region will accept
a VCF object as defined in VariantAnnotation.
library(VariantAnnotation)
fl <- system.file("extdata", "chr22.vcf.gz", package="VariantAnnotation")
r22 = readVcf(fl)
r22## class: CollapsedVCF
## dim: 10376 5
## rowRanges(vcf):
## GRanges with 5 metadata columns: paramRangeID, REF, ALT, QUAL, FILTER
## info(vcf):
## DataFrame with 22 columns: LDAF, AVGPOST, RSQ, ERATE, THETA, CIEND, CIPOS,...
## info(header(vcf)):
## Number Type Description
## LDAF 1 Float MLE Allele Frequency Accounting for LD
## AVGPOST 1 Float Average posterior probability from MaCH/Thunder
## RSQ 1 Float Genotype imputation quality from MaCH/Thunder
## ERATE 1 Float Per-marker Mutation rate from MaCH/Thunder
## THETA 1 Float Per-marker Transition rate from MaCH/Thunder
## CIEND 2 Integer Confidence interval around END for imprecise var...
## CIPOS 2 Integer Confidence interval around POS for imprecise var...
## END 1 Integer End position of the variant described in this re...
## HOMLEN . Integer Length of base pair identical micro-homology at ...
## HOMSEQ . String Sequence of base pair identical micro-homology a...
## SVLEN 1 Integer Difference in length between REF and ALT alleles
## SVTYPE 1 String Type of structural variant
## AC . Integer Alternate Allele Count
## AN 1 Integer Total Allele Count
## AA 1 String Ancestral Allele, ftp://ftp.1000genomes.ebi.ac.u...
## AF 1 Float Global Allele Frequency based on AC/AN
## AMR_AF 1 Float Allele Frequency for samples from AMR based on A...
## ASN_AF 1 Float Allele Frequency for samples from ASN based on A...
## AFR_AF 1 Float Allele Frequency for samples from AFR based on A...
## EUR_AF 1 Float Allele Frequency for samples from EUR based on A...
## VT 1 String indicates what type of variant the line represents
## SNPSOURCE . String indicates if a snp was called when analysing the...
## geno(vcf):
## List of length 3: GT, DS, GL
## geno(header(vcf)):
## Number Type Description
## GT 1 String Genotype
## DS 1 Float Genotype dosage from MaCH/Thunder
## GL G Float Genotype LikelihoodsIn this example we confine attention to single nucleotide variants.
There is a limit of 200 locations in a request, and 55000 requests per hour. We’ll base our query on 100 positions in the chr22 VCF.
dr = which(width(rowRanges(r22))!=1)
r22s = r22[-dr]
res = vep_by_region(r22[1:100], snv_only=FALSE, chk_max=FALSE)
jans = toJSON(content(res))There are various ways to work with the result of this query to the API. We’ll use the rjsoncons JSON processing infrastructure to dig in and understand aspects of the API behavior.
First, the top-level concepts produced for each variant can be retrieved using
## [1] "strand" "end"
## [3] "regulatory_feature_consequences" "id"
## [5] "seq_region_name" "start"
## [7] "most_severe_consequence" "transcript_consequences"
## [9] "assembly_name" "input"
## [11] "allele_string" "motif_feature_consequences"
## [13] "colocated_variants"Annotation of the most severe consequence known will typically be of interest:
##
## 5_prime_UTR_variant intron_variant splice_region_variant
## 1 98 1There is variability in the structure of data returned for each query.
## [[1]]
## regulatory_feature_id variant_allele consequence_terms impact biotype
## 1 ENSR0000.... G regulato.... MODIFIER promoter
##
## [[2]]
## consequence_terms biotype impact regulatory_feature_id variant_allele
## 1 regulato.... promoter MODIFIER ENSR0000.... T
##
## [[3]]
## impact consequence_terms biotype variant_allele regulatory_feature_id
## 1 MODIFIER regulato.... promoter A ENSR0000....
##
## [[4]]
## impact consequence_terms biotype variant_allele regulatory_feature_id
## 1 MODIFIER regulato.... promoter T ENSR0000....
##
## [[5]]
## variant_allele regulatory_feature_id consequence_terms impact biotype
## 1 T ENSR0000.... regulato.... MODIFIER promoter
##
## [[6]]
## consequence_terms biotype impact regulatory_feature_id variant_allele
## 1 regulato.... promoter MODIFIER ENSR0000.... AFurthermore, the content of the motif feature consequences field seems very peculiar.
##
## -0.003 -0.022 -0.087
## 1 1 1
## 1 2 6
## 3 1 1
## 9 A ENSM00205804739
## 1 1 1
## ENSM00494167763 ENSM00522532781 ENSPFM0238
## 1 1 1
## ENSPFM0506 ENSPFM0597 GCM1::MAX
## 1 1 1
## MODIFIER N T
## 3 2 2
## TEAD4::ELF1 TEAD4::ELK1 TEAD4::SPIB
## 1 1 1
## TF_binding_site_variant TFAP2C::MAX Y
## 3 1 1We’ll consider the following approach to converting the API response to a GenomicRanges GRanges instance. Eventually this may become part of the package.
library(GenomicRanges)
.make_GRanges = function( vep_response ) {
stopifnot(inherits(vep_response, "response")) # httr
nested = fromJSON(toJSON(content(vep_response)))
ini = GRanges(seqnames = unlist(nested$seq_region_name),
IRanges(start=unlist(nested$start), end=unlist(nested$end)))
dr = match(c("seq_region_name", "start", "end"), names(nested))
mcols(ini) = DataFrame(nested[,-dr])
ini
}
tstg = .make_GRanges( res )
tstg[,1] # full print is unwieldy## GRanges object with 100 ranges and 1 metadata column:
## seqnames ranges strand | strand
## <Rle> <IRanges> <Rle> | <list>
## [1] 22 50300078 * | 1
## [2] 22 50300086 * | 1
## [3] 22 50300101 * | 1
## [4] 22 50300113 * | 1
## [5] 22 50300166 * | 1
## ... ... ... ... . ...
## [96] 22 50304748 * | 1
## [97] 22 50304805 * | 1
## [98] 22 50304935 * | 1
## [99] 22 50304943 * | 1
## [100] 22 50305084 * | 1
## -------
## seqinfo: 1 sequence from an unspecified genome; no seqlengths## [1] "strand" "regulatory_feature_consequences"
## [3] "id" "most_severe_consequence"
## [5] "transcript_consequences" "assembly_name"
## [7] "input" "allele_string"
## [9] "motif_feature_consequences" "colocated_variants"Now information about variants can be retrieved with range operations. Deep annotation requires nested structure of the metadata columns.
## [[1]]
## impact transcript_id gene_symbol gene_id consequence_terms
## 1 MODIFIER ENST0000.... PLXNB2 ENSG0000.... intron_v....
## 2 MODIFIER ENST0000.... PLXNB2 ENSG0000.... intron_v....
## 3 MODIFIER ENST0000.... PLXNB2 ENSG0000.... intron_v....
## 4 MODIFIER ENST0000.... PLXNB2 ENSG0000.... intron_v....
## biotype gene_symbol_source hgnc_id strand variant_allele flags
## 1 protein_.... HGNC HGNC:9104 -1 G
## 2 protein_.... HGNC HGNC:9104 -1 G cds_end_NF
## 3 protein_.... HGNC HGNC:9104 -1 G cds_end_NF
## 4 protein_.... HGNC HGNC:9104 -1 GAn important element of prior work in ensemblVEP supports feeding annotation back into the VCF used to generate the effect prediction query. This seems feasible but concrete use cases are of interest.
McLaren, William, Laurent Gil, Sarah E. Hunt, Harpreet Singh Riat, Graham R. S. Ritchie, Anja Thormann, Paul Flicek, and Fiona Cunningham. 2016. “The Ensembl Variant Effect Predictor.” Genome Biology 17 (1): 122. https://doi.org/10.1186/s13059-016-0974-4.