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ANNOVAR (version 2016march)

dorun:

Reference:

Select file to annotate:

Must be either a VCF file, or a CG varfile, or a tab-separated file with a 1 line header

Select filetype:

Select Gene Annotation(s):

Use HGVS nomenclature for RefSeq annotation:

if checked, cDNA level annotation is compatible with HGVS

Cytogenic band Annotation?:

This option identifies Giemsa-stained chromosomes bands, (e.g. 1q21.1-q23.3).

Transcription Factor Binding Site Annotation?:

Most Conserved Elements Annotation? (hg18/hg19):

This option phastCons 44-way alignments to annotate variants that fall within conserved genomic regions.

Segmental Duplication Annotation?:

Genetic variants that are mapped to segmental duplications are most likely sequence alignment errors and should be treated with extreme caution.

DGV (Database of Genomic Variants) Annotation?:

Identify previously reported structural variants in DGV (Database of Genomic Variants)

GWAS studies Annotation?:

Identify variants reported in previously published GWAS (Genome-wide association studies)

Select dbSNP version(s) to annotate with:

avSNP are reformatted dbSNP databases with one variant per line and left-normalized indels (for a more detailed discussion read this article: http://annovar.openbioinformatics.org/en/latest/articles/dbSNP/). Flagged SNPs include SNPs less than 1% minor allele frequency (MAF) (or unknown), mapping only once to reference assembly, flagged in dbSnp as clinically associated

Select 1000Genomes Annotation(s):

2012april database for ALL populations was converted to hg18 using the UCSC liftover program

Select Exome Variant Server version(s) to annotate with:

si versions of databases contain indels and chrY calls

Annotate with ExAC 03? (The Exome Aggregation Consortium) (hg18/hg19/hg38):

The Exome Aggregation Consortium (ExAC) is a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a wide variety of large-scale sequencing projects, and to make summary data available for the wider scientific community. The data set provided on this website spans 60,706 unrelated individuals sequenced as part of various disease-specific and population genetic studies. See http://exac.broadinstitute.org/faq for more information.

Annotate with ExAC 03 non-TCGA? (The Exome Aggregation Consortium) (hg18/hg19/hg38):

non-TGCA samples

Annotate with ExAC 03 non-Psych? (The Exome Aggregation Consortium) (hg18/hg19/hg38):

Annotate with GoNL (Genome of the Netherlands) data? (hg19 only):

This is a custom made annotation file, not available from the ANNOVAR website. The database file can be obtained from http://bioinf-galaxian.erasmusmc.nl/public/Data/hg19_gonl.txt

Annotate with SPIDEX database? (hg19 only):

This dataset provides machine-learning prediction on how genetic variants affect RNA splicing. (Xiong et al, Science 2015)

GERP++ Annotation?:

GERP identifies constrained elements in multiple alignments by quantifying substitution deficits (see http://mendel.stanford.edu/SidowLab/downloads/gerp/ for details) This option annotates those variants having GERP++>2 in human genome, as this threshold is typically regarded as evolutionarily conserved and potentially functional

CLINVAR Annotation? (hg19 only):

version 2014-02-11. Annotations include Variant Clinical Significance (unknown, untested, non-pathogenic, probable-non-pathogenic, probable-pathogenic, pathogenic, drug-response, histocompatibility, other) and Variant disease name.

Annotate with NCI60? (hg18/hg19/hg38):

NCI-60 exome allele frequency data

Complete Genomics 46 Genomes? (hg18/hg19):

Diversity Panel; 46 unrelated individuals

Complete Genomics 69 Genomes? (hg18/hg19):

Diversity Panel, Pedigree, YRI trio and PUR trio

Annotate with COSMIC 61? (hg19 only):

Annotate with COSMIC 63? (hg19 only):

Annotate with COSMIC 64? (hg19 only):

Annotate with COSMIC 65? (hg19 only):

Annotate with COSMIC 67? (hg19 only):

Annotate with COSMIC 68? (hg19 only):

Annotate with COSMIC 70? (hg18/hg19/hg38):

Select functional impact scores (LJB2):

LJB refers to Liu, Jian, Boerwinkle paper in Human Mutation, pubmed ID 21520341.

Also get predictions where possible?:

e.g. annotated as -score,damaging- or -score,benign- instead of just score

Annotate with scSNV 1.1 ? (hg19/hg38):

provides splice site effect prediction by AdaBoost and Random Forest

Annotate with Kaviar (23-09-2015)? (hg19/hg38):

170 million variants from 34 projects (13K genomes and 64K exomes)

Annotate with hrcr1 ? (hg19/hg38):

40 million variants from 32K samples

Annotate with MITimpact 2 ? (hg19):

an exhaustive collection of pre-computed pathogenicity predictions of human mitochondrial non-synonymous variants

Annotate with MITimpact 2.4 ? (hg19):

an exhaustive collection of pre-computed pathogenicity predictions of human mitochondrial non-synonymous variants

Annotate with dbNSFP 3.0a ? (hg18/hg19/hg38):

provides whole-genome functional prediction scores on ~20 different algorithms. Now additions to the database include DANN, PROVEAN, fitConsPlease, etc.

Prefix for your output file:

Optional

What it does

This tool will annotate a file using ANNOVAR.

ANNOVAR Website and Documentation

Website: http://www.openbioinformatics.org/annovar/

Paper: http://nar.oxfordjournals.org/content/38/16/e164

Input Formats

Input Formats may be one of the following:

VCF file Complete Genomics varfile

Custom tab-delimited file (specify chromosome, start, end, reference allele, observed allele columns)

Custom tab-delimited CG-derived file (specify chromosome, start, end, reference allele, observed allele, varType columns)

Database Notes

see ANNOVAR website for extensive documentation, a few notes on some of the databases:

LJB2 Database

PolyPhen2 HVAR should be used for diagnostics of Mendelian diseases, which requires distinguishing mutations with drastic effects from all the remaining human variation, including abundant mildly deleterious alleles.The authors recommend calling probably damaging if the score is between 0.909 and 1, and possibly damaging if the score is between 0.447 and 0.908, and benign if the score is between 0 and 0.446.

PolyPhen HDIV should be used when evaluating rare alleles at loci potentially involved in complex phenotypes, dense mapping of regions identified by genome-wide association studies, and analysis of natural selection from sequence data. The authors recommend calling probably damaging if the score is between 0.957 and 1, and possibly damaging if the score is between 0.453 and 0.956, and benign is the score is between 0 and 0.452.