<tool id="snpSift_dbnsfp_generic" name="SnpSift dbNSFP" version="@WRAPPER_VERSION@.1">
    <description>Add Annotations from dbNSFP and similar annotation DBs</description>
    <macros>
        <import>snpSift_macros.xml</import>
    </macros>
    <expand macro="requirements" />
    <expand macro="stdio" />
    <expand macro="version_command" />
    <command><![CDATA[
        @CONDA_SNPSIFT_JAR_PATH@ &&
        java -Xmx6G -jar "\$SNPSIFT_JAR_PATH/SnpSift.jar" dbnsfp -v
        #if $db.dbsrc == 'cached':
          -db $db.dbnsfp 
          #if $db.annotations and str($db.annotations) != '':
            -f "$db.annotations"
          #end if
        #else:
          -db "${db.dbnsfpdb.extra_files_path}/${db.dbnsfpdb.metadata.bgzip}"
          #if $db.annotations and str($db.annotations) != '':
            -f "$db.annotations"
          #end if
        #end if
        "$input" > "$output"
        2> tmp.err && grep -v file tmp.err
]]>
    </command>
    <inputs>
        <param name="input" type="data" format="vcf" label="Variant input file in VCF format"/>
        <conditional name="db">
            <param name="dbsrc" type="select" label="dbNSFP ">
                <option value="cached">Locally installed dbNSFP database </option>
                <option value="history">dbNSFP database from your history</option>
            </param>
            <when value="cached">
                <param name="dbnsfp" type="select" label="Genome">
                    <options from_data_table="snpsift_dbnsfp">
                        <column name="name" index="2"/>
                        <column name="value" index="3"/>
                    </options>
                </param>
                <param name="annotations" type="select" multiple="true" display="checkboxes" label="Annotate with">
                    <options from_data_table="snpsift_dbnsfp">
                        <column name="name" index="3"/>
                        <column name="value" index="3"/>
                        <filter type="param_value" ref="dbnsfp" column="2" />
                        <filter type="multiple_splitter" column="3" separator=","/>
                    </options>
                </param>
            </when>
            <when value="history">
                <param name="dbnsfpdb" type="data" format="snpsiftdbnsfp" label="DbNSFP"/>
                <param name="annotations" type="select" multiple="true" display="checkboxes" label="Annotate with">
                  <options>
                    <filter type="data_meta" ref="dbnsfpdb" key="annotation" />
                  </options>
                </param>
            </when>
        </conditional>
    </inputs>
    <outputs>
        <data format="vcf" name="output" />
    </outputs>
    <tests>
        <!-- This cannot be tested at the moment because test_dbnsfpdb.tabular
             is converted from dbnsfp.tabular to snpsiftdbnsfp format on-the-fly
             when this tool is run and annotation metadata is not available
             until after the conversion is completed.
        <test>
            <param name="input" ftype="vcf" value="test_annotate_in.vcf"/>
            <param name="dbsrc" value="history"/>
            <param name="dbnsfpdb" value="test_dbnsfpdb.tabular" ftype="dbnsfp.tabular" />
            <param name="annotations" value="aaref,aaalt,genename,aapos,SIFT_score"/>
            <output name="output">
                <assert_contents>
                    <has_text text="dbNSFP_SIFT_score=0.15" />
                </assert_contents>
            </output>
        </test> -->
    </tests>
    <help><![CDATA[

The dbNSFP is an integrated database of functional predictions from multiple algorithms (SIFT, Polyphen2, LRT and MutationTaster, PhyloP and GERP++, etc.).
It contains variant annotations such as:


  1000Gp1_AC
    Alternative allele counts in the whole 1000 genomes phase 1 (1000Gp1) data
  1000Gp1_AF
    Alternative allele frequency in the whole 1000Gp1 data
  1000Gp1_AFR_AC
    Alternative allele counts in the 1000Gp1 African descendent samples
  1000Gp1_AFR_AF
    Alternative allele frequency in the 1000Gp1 African descendent samples
  1000Gp1_AMR_AC
    Alternative allele counts in the 1000Gp1 American descendent samples
  1000Gp1_AMR_AF
    Alternative allele frequency in the 1000Gp1 American descendent samples
  1000Gp1_ASN_AC
    Alternative allele counts in the 1000Gp1 Asian descendent samples
  1000Gp1_ASN_AF
    Alternative allele frequency in the 1000Gp1 Asian descendent samples
  1000Gp1_EUR_AC
    Alternative allele counts in the 1000Gp1 European descendent samples
  1000Gp1_EUR_AF
    Alternative allele frequency in the 1000Gp1 European descendent samples
  aaalt
    Alternative amino acid. "." if the variant is a splicing site SNP (2bp on each end of an intron)
  aapos
    Amino acid position as to the protein. "-1" if the variant is a splicing site SNP (2bp on each end of an intron)
  aapos_SIFT
    ENSP id and amino acid positions corresponding to SIFT scores. Multiple entries separated by ";"
  aapos_FATHMM
    ENSP id and amino acid positions corresponding to FATHMM scores. Multiple entries separated by ";"
  aaref
    Reference amino acid. "." if the variant is a splicing site SNP (2bp on each end of an intron)
  alt
    Alternative nucleotide allele (as on the + strand)
  Ancestral_allele
    Ancestral allele (based on 1000 genomes reference data)
  cds_strand
    Coding sequence (CDS) strand (+ or -)
  chr
    Chromosome number
  codonpos
    Position on the codon (1, 2 or 3)
  Ensembl_geneid
    Ensembl gene ID
  Ensembl_transcriptid
    Ensembl transcript IDs (separated by ";")
  ESP6500_AA_AF
    Alternative allele frequency in the African American samples of the NHLBI GO Exome Sequencing Project (ESP6500 data set)
  ESP6500_EA_AF
    Alternative allele frequency in the European American samples of the NHLBI GO Exome Sequencing Project (ESP6500 data set)
  FATHMM_pred
    If a FATHMM_score is <=-1.5 (or rankscore <=0.81415) the corresponding non-synonymous SNP is predicted as "D(AMAGING)"; otherwise it is predicted as "T(OLERATED)". Multiple predictions separated by ";"
  FATHMM_rankscore
    FATHMMori scores were ranked among all FATHMMori scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of FATHMMori scores in dbNSFP. If there are multiple scores, only the most damaging (largest) rankscore is presented. The scores range from 0 to 1
  FATHMM_score
    FATHMM default score (FATHMMori)
  fold-degenerate
    Degenerate type (0, 2 or 3)
  genename
    Gene name; if the non-synonymous SNP can be assigned to multiple genes, gene names are separated by ";"
  GERP++_NR
    GERP++ neutral rate
  GERP++_RS
    GERP++ RS score, the larger the score, the more conserved the site
  GERP++_RS_rankscore
    GERP++ RS scores were ranked among all GERP++ RS scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of GERP++ RS scores in dbNSFP
  hg18_pos(1-coor)
    Physical position on the chromosome as to hg18 (1-based coordinate)
  Interpro_domain
    Domain or conserved site on which the variant locates
  LR_pred
    Prediction of our LR based ensemble prediction score, "T(olerated)" or "D(amaging)". The score cutoff between "D" and "T" is 0.5. The rankscore cutoff between "D" and "T" is 0.82268
  LR_rankscore
    LR scores were ranked among all LR scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of LR scores in dbNSFP. The scores range from 0 to 1
  LR_score
    Our logistic regression (LR) based ensemble prediction score, which incorporated 10 scores (SIFT, PolyPhen-2 HDIV, PolyPhen-2 HVAR, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy, PhyloP) and the maximum frequency observed in the 1000 genomes populations. Larger value means the SNV is more likely to be damaging. Scores range from 0 to 1
  LRT_Omega
    Estimated nonsynonymous-to-synonymous-rate ratio (Omega, reported by LRT)
  LRT_converted_rankscore
    LRTori scores were first converted as LRTnew=1-LRTori*0.5 if Omega<1, or LRTnew=LRTori*0.5 if Omega>=1. Then LRTnew scores were ranked among all LRTnew scores in dbNSFP. The rankscore is the ratio of the rank over the total number of the scores in dbNSFP. The scores range from 0.00166 to 0.85682
  LRT_pred
    LRT prediction, D(eleterious), N(eutral) or U(nknown), which is not solely determined by the score
  LRT_score
    The original LRT two-sided p-value (LRTori), ranges from 0 to 1
  MutationAssessor_pred
    MutationAssessor's functional impact of a variant
  MutationAssessor_rankscore
    MAori scores were ranked among all MAori scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of MAori scores in dbNSFP. The scores range from 0 to 1
  MutationAssessor_score
    MutationAssessor functional impact combined score (MAori)
  MutationTaster_converted_rankscore
    The MTori scores were first converted: if the prediction is "A" or "D" MTnew=MTori; if the prediction is "N" or "P", MTnew=1-MTori. Then MTnew scores were ranked among all MTnew scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of MTnew scores in dbNSFP. The scores range from 0.0931 to 0.80722
  MutationTaster_pred
    MutationTaster prediction
  MutationTaster_score
    MutationTaster p-value (MTori), ranges from 0 to 1
  phastCons46way_placental
    phastCons conservation score based on the multiple alignments of 33 placental mammal genomes (including human). The larger the score, the more conserved the site
  phastCons46way_placental_rankscore
    phastCons46way_placental scores were ranked among all phastCons46way_placental scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of phastCons46way_placental scores in dbNSFP
  phastCons46way_primate
    phastCons conservation score based on the multiple alignments of 10 primate genomes (including human). The larger the score, the more conserved the site
  phastCons46way_primate_rankscore
    phastCons46way_primate scores were ranked among all phastCons46way_primate scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of phastCons46way_primate scores in dbNSFP
  phastCons100way_vertebrate
    phastCons conservation score based on the multiple alignments of 100 vertebrate genomes (including human). The larger the score, the more conserved the site
  phastCons100way_vertebrate_rankscore
    phastCons100way_vertebrate scores were ranked among all phastCons100way_vertebrate scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of phastCons100way_vertebrate scores in dbNSFP
  phyloP46way_placental
    phyloP (phylogenetic p-values) conservation score based on the multiple alignments of 33 placental mammal genomes (including human). The larger the score, the more conserved the site
  phyloP46way_placental_rankscore
    phyloP46way_placental scores were ranked among all phyloP46way_placental scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of phyloP46way_placental scores in dbNSFP
  phyloP46way_primate
    phyloP (phylogenetic p-values) conservation score based on the multiple alignments of 10 primate genomes (including human). The larger the score, the more conserved the site
  phyloP46way_primate_rankscore
    phyloP46way_primate scores were ranked among all phyloP46way_primate scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of phyloP46way_primate scores in dbNSFP
  phyloP100way_vertebrate
    phyloP (phylogenetic p-values) conservation score based on the multiple alignments of 100 vertebrate genomes (including human). The larger the score, the more conserved the site
  phyloP100way_vertebrate_rankscore
    phyloP100way_vertebrate scores were ranked among all phyloP100way_vertebrate scores in dbNSFP. The rankscore is the ratio of the rank of the score over the total number of phyloP100way_vertebrate scores in dbNSFP
  Polyphen2_HDIV_pred
    Polyphen2 prediction based on HumDiv
  Polyphen2_HDIV_rankscore
    Polyphen2 HDIV scores were first ranked among all HDIV scores in dbNSFP. The rankscore is the ratio of the rank the score over the total number of the scores in dbNSFP. If there are multiple scores, only the most damaging (largest) rankscore is presented. The scores range from 0.02656 to 0.89917
  Polyphen2_HDIV_score
    Polyphen2 score based on HumDiv, i.e. hdiv_prob. The score ranges from 0 to 1. Multiple entries separated by ";"
  Polyphen2_HVAR_pred
    Polyphen2 prediction based on HumVar
  Polyphen2_HVAR_rankscore
    Polyphen2 HVAR scores were first ranked among all HVAR scores in dbNSFP. The rankscore is the ratio of the rank the score over the total number of the scores in dbNSFP. If there are multiple scores, only the most damaging (largest) rankscore is presented. The scores range from 0.01281 to 0.9711
  Polyphen2_HVAR_score
    Polyphen2 score based on HumVar, i.e. hvar_prob. The score ranges from 0 to 1. Multiple entries separated by ";"
  pos(1-coor)
    Physical position on the chromosome as to hg19 (1-based coordinate)
  RadialSVM_pred
    Prediction of our SVM based ensemble prediction score, "T(olerated)" or "D(amaging)". The score cutoff between "D" and "T" is 0. The rankscore cutoff between "D" and "T" is 0.83357
  RadialSVM_rankscore
    RadialSVM scores were ranked among all RadialSVM scores in dbNSFP. The rankscore is the ratio of the rank of the screo over the total number of RadialSVM scores in dbNSFP. The scores range from 0 to 1
  RadialSVM_score
    Our support vector machine (SVM) based ensemble prediction score, which incorporated 10 scores (SIFT, PolyPhen-2 HDIV, PolyPhen-2 HVAR, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy, PhyloP) and the maximum frequency observed in the 1000 genomes populations. Larger value means the SNV is more likely to be damaging. Scores range from -2 to 3 in dbNSFP
  ref
    Reference nucleotide allele (as on the + strand)
  refcodon
    Reference codon
  Reliability_index
    Number of observed component scores (except the maximum frequency in the 1000 genomes populations) for RadialSVM and LR. Ranges from 1 to 10. As RadialSVM and LR scores are calculated based on imputed data, the less missing component scores, the higher the reliability of the scores and predictions
  SIFT_converted_rankscore
    SIFTori scores were first converted to SIFTnew=1-SIFTori, then ranked among all SIFTnew scores in dbNSFP. The rankscore is the ratio of the rank the SIFTnew score over the total number of SIFTnew scores in dbNSFP. If there are multiple scores, only the most damaging (largest) rankscore is presented. The rankscores range from 0.02654 to 0.87932
  SIFT_pred
    If SIFTori is smaller than 0.05 (rankscore>0.55) the corresponding non-synonymous SNP is predicted as "D(amaging)"; otherwise it is predicted as "T(olerated)". Multiple predictions separated by ";"
  SIFT_score
    SIFT score (SIFTori). Scores range from 0 to 1. The smaller the score the more likely the SNP has damaging effect. Multiple scores separated by ";"
  SiPhy_29way_logOdds
    SiPhy score based on 29 mammals genomes. The larger the score, the more conserved the site
  SiPhy_29way_pi
    The estimated stationary distribution of A, C, G and T at the site, using SiPhy algorithm based on 29 mammals genomes
  SLR_test_statistic
    SLR test statistic for testing natural selection on codons. A negative value indicates negative selection, and a positive value indicates positive selection. Larger magnitude of the value suggests stronger evidence
  Uniprot_aapos
    Amino acid position as to Uniprot. Multiple entries separated by ";"
  Uniprot_acc
    Uniprot accession number. Multiple entries separated by ";"
  Uniprot_id
    Uniprot ID number. Multiple entries separated by ";"
  UniSNP_ids
    rs numbers from UniSNP, which is a cleaned version of dbSNP build 129, in format: rs number1;rs number2;...


The procedure for preparing the dbNSFP data for use in SnpSift dbnsfp and a couple of prebuilt dbNSFP databases are available at:
http://snpeff.sourceforge.net/SnpSift.html#dbNSFP


**Uploading Your Own Annotations for any Genome**

The website for dbNSFP databases releases is:  
https://sites.google.com/site/jpopgen/dbNSFP

But there is only annotation for human hg18, hg19,  and hg38 genome builds. 

However, any dbNSFP-like tabular file that be can used with SnpSift dbnsfp if it has:

  - The first line of the file must be column headers that name the annotations.  
  - The first 4 columns are required and must be:

    1. #chr		- chromosome 
    2. pos(1-coor)	- position in chromosome
    3. ref		- reference base
    4. alt		- alternate base


For example:

::

	#chr	pos(1-coor)	ref	alt	aaref	aaalt	genename	SIFT_score
	  4	 100239319	 T	 A	  H	  L	 ADH1B	           0
	  4	 100239319	 T	 C	  H	  R	 ADH1B	           0.15
	  4	 100239319	 T	 G	  H	  P	 ADH1B	           0


The custom galaxy datatypes for dbNSFP can automatically convert the specially formatted tabular file for use by SnpSift dbNSFP:
  1. Upload the tabular file, set the datatype as: **"dbnsfp.tabular"**
  2. Edit the history dataset attributes (pencil icon): Use "Convert Format" to convert the **"dbnsfp.tabular"** to the correct format for SnpSift dbnsfp: **"snpsiftdbnsfp"**.

The procedure for preparing the dbNSFP data for use in SnpSift dbnsfp is in the SnpSift documentation.


@EXTERNAL_DOCUMENTATION@
	http://snpeff.sourceforge.net/SnpSift.html#dbNSFP
]]>
    </help>
    <expand macro="citations">
        <citation type="doi">DOI: 10.1002/humu.21517</citation>
        <citation type="doi">DOI: 10.1002/humu.22376</citation>
        <citation type="doi">DOI: 10.1002/humu.22932</citation>
        <citation type="doi">doi: 10.1093/hmg/ddu733</citation>
        <citation type="doi">doi: 10.1093/nar/gku1206</citation>
        <citation type="doi">doi: 10.3389/fgene.2012.00035</citation>
    </expand>
</tool>