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<!DOCTYPE html>
<!--[if lt IE 7]> <html class="lt-ie9 lt-ie8 lt-ie7"> <![endif]-->
<!--[if IE 7]> <html class="lt-ie9 lt-ie8"> <![endif]-->
<!--[if IE 8]> <html class="lt-ie9"> <![endif]-->
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<head>
<title>fathmm - Analyze dbSNP/Protein Missense Variants</title>
<meta charset="utf-8">
<meta name="viewport" content="width=device-width, initial-scale=1.0">
<meta name="description" content="Analyze dbSNP/Protein Missense Variants">
<meta name="keywords" content="Inherited Disease, Missense Mutation, Amino Acid Substitutions, Hidden Markov Models, HMMs, Single Nucleotide Polymorphisms, SNPs, Non Synonymous Mutation, nsSNPs, fathmm">
<meta name="author" content="Hashem A. Shihab">
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<div class="hero-unit">
<h2>Analyze Protein Missense Variants</h2>
</div>
<ul class="nav nav-tabs" id="myTab">
<li id="new-tab" class="active">
<a href="#new" onclick="javascript: remove();" data-toggle="tab">New Submission</a>
</li>
<li id="eg-tab">
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<legend><h3>Enter Your Mutations:</h3></legend>
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<option value="INHERITED" selected>Weighted</option>
<option value="UNWEIGHTED">Unweighted</option>
</select>
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<option value="">None</option>
<option value="DO" selected>Disease Ontology</option>
<option value="GO">Gene Ontology</option>
<option value="HP">Human Phenotype Ontology</option>
<option value="MP">Mouse Phenotype Ontology</option>
<option value="WP">Worm Phenotype Ontology</option>
<option value="YP">Yeast Phenotype Ontology</option>
<option value="FP">Fly Phenotype Ontology</option>
<option value="FA">Fly Anatomy Ontology</option>
<option value="ZA">Zebrafish Anatomy Ontology</option>
<option value="AP">Arabidopsis Plant Ontology</option>
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<li><a href="#overview"><i class="icon-chevron-right"></i> Overview</a></li>
<li><a href="#format"><i class="icon-chevron-right"></i> Input Format</a></li>
<li><a href="#format_batch"><i class="icon-chevron-right"></i> Batch Submission</a></li>
<li><a href="#algorithm"><i class="icon-chevron-right"></i> Prediction Algorithm</a></li>
<li><a href="#phenotype"><i class="icon-chevron-right"></i> Phenotypic Associations</a></li>
<li><a href="#vcf"><i class="icon-chevron-right"></i> Annotating VCF's</a></li>
</ul>
</div>
<div class="span9">
<section id="overview">
<h1>Overview:</h1>
<br />
<p>
The Functional Analysis through Hidden Markov Models (fathmm) software and server is is capable of <b>predicting the functional
effects of protein missense mutations</b> by combining sequence conservation within hidden Markov models (HMMs), representing the
alignment of homologous sequences and conserved protein domains, with "pathogenicity weights", representing the overall tolerance
of the corresponding model to mutations.
<br /><br />
For more information, please refer to the following publication:
<br /><br />
Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GLA, Edwards KJ, Day INM, Gaunt, TR. (2013). Predicting the Functional, Molecular and Phenotypic
Consequences of Amino Acid Substitutions using Hidden Markov Models. <i>Hum. Mutat.</i>, <b>34</b>:57-65
<a href="http://www.ncbi.nlm.nih.gov/pubmed/23033316"><img src="./img/pubmed.png" alt="fathmm Paper"></a>
</p>
<br />
<a href='./inherited.html#top'>Back to Top ...</a>
</section>
<br />
<section id="format">
<h1>Input Format:</h1>
<br />
<p>
Our software accepts one of the following formats (see <a href="./about.html#vcf">here</a> for annotating VCF files):
<br /><br />
<ul>
<li>
<code><protein> <substitution></code>
</li>
<li>
<code>dbSNP rs identifiers</code>
</li>
</ul>
<br />
In the above, <code><protein></code> is the protein identifier and <code><substitution></code> is the amino acid substitution in the conventional one
letter format. At present, <b>our server accepts SwissProt/TrEMBL, RefSeq and Ensembl protein identifiers</b>, e.g.:
<br /><br />
<pre>
P43026 L441P
</pre>
or:
<br /><br />
<pre>
rs137854462
</pre>
</p>
<br />
<a href='./inherited.html#top'>Back to Top ...</a>
</section>
<br />
<section id="format_batch">
<h1>Batch Submission:</h1>
<br />
<p>
<b>
It is possible to submit multiple amino acid substitutions as a 'Batch Submission' via our server</b>. Here, all amino acid substitutions for a protein can be
entered on a single line and should be separated by a comma, e.g:
<br /><br />
<pre>
P43026 L441P
ENSP00000325527 N548I,E1073K,C2307S
</pre>
<br />
<b>Note: this option is not available when analysing dbSNP rs identifiers</b>.
</p>
<br />
<a href='./inherited.html#top'>Back to Top ...</a>
</section>
<br />
<section id="algorithm">
<h1>Prediction Algorithm:</h1>
<br />
<p>
As described in our paper, <b>our software is comprised of two algorithms</b>: <b>one sequence/conservation based (Unweighted) and the other
combines our Unweighted algorithm with pathogenicity weights (Weighted)</b>. In short, our Weighted algorithm is capable of adjusting
our conservation-based predictions to account for the tolerance of related sequences to mutations. For example, mutations falling within
diverse regions of the Cellular Tumor Antigen P53 can be up-weighted according to the critical role the protein plays in cell regulation.
In contrast, mutations falling within conserved regions of the MHC Antigen-Regognition Domain can be down-weighted according the
hypervariable nature of the domain.
</p>
<br />
<a href='./inherited.html#top'>Back to Top ...</a>
</section>
<br />
<section id="phenotype">
<h1>Phenotype Associations:</h1>
<br />
<p>
<b>Our software not only predicts the potentially deleterious nature of protein variants but it is also capable of annotating
the molecular and phenotypic consequences of these mutations</b> via several domain-centric ontologies (<a href="http://supfam.org/SUPERFAMILY/dcGO/"><b>dcGO</b></a>).
Here, the molecular consequences of mutations are statistically inferred by mapping <a href="http://supfam.cs.bris.ac.uk/SUPERFAMILY/"><b>SUPERFAMILY</b></a>
domains onto the Gene Ontology, the Human Phenotype Ontology and the Mammalian Phenotype Ontology (and more).
<br /><br />
For more information on these mappings, please refer to the following publications:
<br /><br />
Fang H, Gough J. (2012). dcGO: database of domain-centric ontologies on functions, phenotypes, diseases and more. <i>Nucleic Acids Res.</i>, <b>41</b>, D536-544.
<br /><br />
Gough J, Karplus K, Hughey R, Chothia C. (2001). Assignment of homology to genome sequences using a library of hidden Markov models that represent all proteins of known structure. <i>J. Mol. Biol.</i>, <b>313</b>, 903-919.
</p>
<br />
<a href='./inherited.html#top'>Back to Top ...</a>
</section>
<br />
<section id="vcf">
<h1>VCF Annotation:</h1>
<br />
<p>
Unfortunately, due to disk space constraints, we are unable to annotate Variant Call Format (VCF) files on your behalf. However, the consequences of all VCF variants
can be derived using the <b><a href="http://www.ensembl.org/info/docs/variation/vep/index.html">Ensembl Variant Effect Predictor (VEP)</a></b>.
Once annotated, the following script <b><a href="./parseVCF.py">(available here)</a></b> is capable of parsing these annotations and will provide you with a list of protein
consequences which can then be used as input into our server/software.
<br /><br />
Additional help on using our script is available by typing the following command:
<br /><br />
<pre>python parseVCF.py --help</pre>
</p>
<br />
<a href='./inherited.html#top'>Back to Top ...</a>
</section>
</div>
</div>
</div>
</div>
<hr>
<footer>
<p>
If you have found this resource useful, please cite the following work:
<br />
<a href="http://www.ncbi.nlm.nih.gov/pubmed/23033316">Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GLA, Edwards KJ, Day INM, Gaunt, TR. (2013). Predicting the Functional, Molecular and Phenotypic Consequences of Amino Acid Substitutions using Hidden Markov Models. Hum. Mutat., <b>34</b>, 57-65 </a>
</p>
<p>
We welcome any comments and/or suggestions that you may have regarding our software and server - please send an email directly to [email protected]
</p>
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