<big>This app is being upgraded and is not currently available. Instead, please use <a href="/knowledge-center/data-viewer">Genome Explorer</a>, which is new functionality at Sequencing.com that provides similar information as this app.</big>Clinical annotations of genomic variants This app analyzes human genetic data and provides clinical annotations of variants that is consistent with the principles of the Human Genome Variation Society (HGVS) guidelines.The app utilizes multithreaded cloud computing technology to provide clinical annotations for almost all genetic data (Next-Generation Sequencing (NGS) including Whole Genome and Exome as well as genotyping microarrays).

<big>Inputs</big><ul style="margin-left:40px"><li>VCF v4.1 file containing human genetic data</li><li>Reference genome used to create the VCF file -OR- select Reference Genome 'Auto Detect' as the reference genome will be automatically determined</li><li>If a specific set of genes is needed, add a genelist.txt file. If this is not added then all genes will be included. <ul><li>File must contain one human gene symbol per row</li><li>File must be in .txt format</li><li>Upload your genelist.txt file to your Sequencing.com account and then when you start this app select 'Modify parameters' (appears above the 'Submit' button). Then select the option to define genes and select your genelist.txt file.</li></ul></li>
</ul><big>Outputs</big><ul style="margin-left:40px"><li>CSV file (TAB delimited TXT file)</li><li>Every line of the CSV file represents a single variant call</li><li>CSV file will contain the following columns:</li>
</ul><ol style="margin-left:80px"><li>ID (Variant call ID taken from the input file)</li><li>CHROM (chromosome of variant)</li><li>POS (genomic coordinate of variant)</li><li>REF (reference allele of variant)</li><li>ALT (alternative allele of variant)</li><li>QUAL (QUAL value in the input VCF record)</li><li>FILTER (FILTER value in the input VCF record)</li><li>TYPE (value of TYPE annotation flag)</li><li>ENST (value of ENST annotation flag)</li><li>GENE (value of GENE annotation flag)</li><li>TRINFO (value of TRINFO annotation flag)</li><li>LOC (value of LOC annotation flag)</li><li>CSN (value of CSN annotation flag)</li><li>CLASS (value of CLASS annotation flag)</li><li>SO (value of SO annotation flag)</li><li>IMPACT (value of IMPACT annotation flag)</li><li>ALTFLAG (value of ALTFLAG annotation flag)</li><li>ALTCLASS (value of ALTCLASS annotation flag)</li><li>ALTSO (value of ALTSO annotation flag)</li><li>DBSNP (value of DBSNP annotation flag)</li>
</ol>

<big>Multiallelic calls and/or multiple transcripts </big>Every line of the output CSV file represents a single variant call. Unlike in the VCF format, annotation information for multiallelic variant calls are split to multiple lines (Example 1). If a variant call overlaps with multiple transcripts, the information is also split into multiple records (Example 2).<big>Example 1</big>For the single VCF record describing a 1-base deletion and a 1-base insertion:<table border="1" cellpadding="1" cellspacing="1" style="width:500px"><tbody><tr><td>#CHROM</td><td>POS</td><td>ID</td><td>REF</td><td>ALT</td><td>Additional columns...</td></tr><tr><td>8</td><td>3443799</td><td>.</td><td>GA</td><td>G,GAA</td><td>Additional data...</td></tr></tbody>
</table> two lines will be added to the output CSV file:<table border="1" cellpadding="1" cellspacing="1" style="width:500px"><tbody><tr><td>ID</td><td>CHROM</td><td>POS</td><td>REF</td><td>ALT</td><td>QUAL</td><td>FILTER</td><td>TYPE</td><td>ENST</td><td>GENE</td><td>Additional columns...</td></tr><tr><td>.</td><td>8</td><td>3443799</td><td>GA</td><td>G</td><td>42</td><td>PASS</td><td>Deletion</td><td>ENST00000537824</td><td>CSMD1</td><td>Additional data...</td></tr><tr><td>.</td><td>8</td><td>3443799</td><td>GA</td><td>GAA</td><td>42</td><td>Pass</td><td>Insertion</td><td>ENST00000537824</td><td>CSMD1</td><td>Additional data...</td></tr></tbody>
</table> The TYPE and CSN annotation flags are given as follows:<ul><li>TYPE=Deletion,Insertion</li><li>CSN=c.1098-18delT,c.1098-18dupT;</li>
</ul> <big>Example 2</big>For the single VCF record describing a triallelic substitution that overlaps with two transcripts (ENST00000325203 and ENST00000344683) in the whole exome set:<table border="1" cellpadding="1" cellspacing="1" style="width:500px"><tbody><tr><td>#CHROM</td><td>POS</td><td>ID</td><td>REF</td><td>ALT</td><td>Additional columns...</td></tr><tr><td>8</td><td>6389889</td><td>.</td><td>C</td><td>G,A</td><td>Additional data...</td></tr></tbody>
</table> four lines will be added to the output CSV file:<table border="1" cellpadding="1" cellspacing="1" style="width:500px"><tbody><tr><td>ID</td><td>CHROM</td><td>POS</td><td>REF</td><td>ALT</td><td>QUAL</td><td>FILTER</td><td>TYPE</td><td>ENST</td><td>GENE</td><td>Additional columns...</td></tr><tr><td>.</td><td>8</td><td>6389889</td><td>C</td><td>G</td><td>200</td><td>PASS</td><td>SUBSTITUTION</td><td>ENST00000325203</td><td>ANGPT2</td><td>Additional data...</td></tr><tr><td>.</td><td>8</td><td>6389889</td><td>C</td><td>G</td><td>200</td><td>PASS</td><td>SUBSTITUTION</td><td>ENST00000344683</td><td>MCPH1</td><td>Additional data...</td></tr><tr><td>.</td><td>8</td><td>6389889</td><td>C</td><td>A</td><td>200</td><td>PASS</td><td>SUBSTITUTION</td><td>ENST00000325203</td><td>ANGPT2</td><td>Additional data...</td></tr><tr><td>.</td><td>8</td><td>6389889</td><td>C</td><td>A</td><td>200</td><td>PASS</td><td>SUBSTITUTION</td><td>ENST00000344683</td><td>MCPH1</td><td>Additional data...</td></tr></tbody>
</table> The GENE, LOC and CSN annotation flags are given as follows:<ul><li>GENE=ANGPT2:MCPH1,ANGPT2:MCPH1</li><li>LOC=Ex2:In12/13,Ex2:In12/13</li><li>CSN=c.408G&gt;C_p.=:c.2214+32439C&gt;G,c.408G&gt;T_p.=:c.2214+32439C&gt;A</li><li>Note that both alternative alleles in both genes (ANGPT2 and MCPH1) cause synonymous and intronic changes, respectively.</li>
</ul>

This app utilizes CAVA v1.1.0.Márton Münz, Elise Ruark, Anthony Renwick, Emma Ramsay, Matthew Clarke, Shazia Mahamdallie, Victoria Cloke, Sheila Seal, Ann Strydom, Gerton Lunter, Nazneen Rahman. (2015) CSN and CAVA: variant annotation tools for rapid, robust next-generation sequencing analysis in the clinical setting. Genome Medicine 7:76, <a href="http://www.genomemedicine.com/content/7/1/76" >doi:10.1186/s13073-015-0195-6</a>.

Clinical Annotator of Variants

Analyzes human genetic data and provides clinical annotations of variants that is consistent with the principles of the Human Genome Variation Society (HGVS) guidelines.