Introduction to Clinical Genomics

 
 

This class describes how to access information about genes and their variants associated with diseases. It also describes the impact of variants on drug response and dosing guidelines.

Topics to be covered:

  • Introduction to resources, such as ClinVar, Clinical Genomic Database (CGD), dbSNP, Online Mendelian Inheritance in Man (OMIM), Exom Variant Server (EVS), and Genetic Testing Registry (GTR), to access information about genes and their variants associated with diseases
     
  • Introduction to resources, such as Clinical Pharmacogenetics Implementation Consortium (CPIC), and Pharmacogenomics Knowledgebase (PharmGKB), to obtain information about the impact of variants on drug response and dosing guidelines
     
  • Introduction to resources, such as Combined Annotation Dependent Depletion (CADD), for functional, pathogenicity, or deleteriousness annotation of variants

Introduction to resources to access information about genes and their variants associated with diseases

Search for “thiopurine S-methyl transferase deficiency” in Clinical Genomic Database (http://research.nhgri.nih.gov/CGD/). Click on the TPMT gene link.

Click on the EVS link and then on the “display snp summary” button. Note the T>C genome variant with dbSNP id rs1142345 at position 719 on transcript NM_000367.2 causing Y240C change in the corresponding protein sequence. Also, note the prediction of effect of amino acid change by GERP, Grantham scores, and PolyPhen2. 

Go back to the CGD page. Click on the OMIM link. Scroll down to the ALLELIC VARIANTS section. The variant Tyr240Cys is referred to as TPMT*3C. We will get the list of all variant names later. 

Go back to the CGD results page. Click on the dbSNP link. Select the Clinical Source box and click on the Refresh button.   

Go back to the CGD results page and click on the 1000 Genomes link. Click on the Get VCF data link.  Click on the Next button. Right click on the file name and choose Save link as from the menu.   The file is here

Go back to the CGD results page and click on the ClinVar link. Click on the See details link for the Tyr240Cys variant. 

From the ClinVar page for TPMT Tyr240Cys, click on the Gene link. TPMT metabolizes thiopuringe drugs such as 6-meracptopurine by methylating them. 

Click on the Locus-specific Databases link under the Additional links menu and then on the TPMT homepage-Mendelian genes. Click on the External link #1 TPMT allele nomenclature. Click on the table of TPMT alleles.

Go back to the Gene database results page. Click on the GTR link. 

Introduction to resources to obtain information about the impact of variants on drug
response and dosing guidelines

Go back to the Gene database results page. Click on the PharmGKB link. Click on the Pathways link.  Go back to the PharmGKB results page.
Click on the Haplotypes page. Go back to the results page.
Investigate tabs under the Clinical PGx tab: Drug Labels and Clinical AnnotationsIf you log in, you will see additional information.

Click on the Dosing Guidelines tab and then on the CPIC Dosing Guideline for azathiopurine and TPMT.
 

Introduction to resources, such as Combined Annotation Dependent Depletion (CADD), for functional, pathogenicity, or deleteriousness annotation of variants

Access the Combined Annotation Dependent Depletion (CADD) page.   http://cadd.gs.washington.edu/home .  Click on the Score variants link. Browse the vcf file saved earlier, select the box “Include underlying annotation in the output” and then on the upload variants button. 

Save the results file, extract it and open in excel.  Sort the file by PHRED score highest to lowest. Change the labeling of the Excel columns to numbers, if necessary, by using File—/Options—/Formulas—.  Check the box for R1C1 reference style under the Working with formulas menu.

All columns are described in http://cadd.gs.washington.edu/static/ReleaseNotes_CADD_v1.2.pdf.

Other resources

Variant Effect Predictor: http://www.ensembl.org/info/docs/tools/vep/index.html

wANNOVAR: http://wannovar.wglab.org/

SDM http://www-cryst.bioc.cam.ac.uk/~sdm/sdm.php

The Phenotype-Genotype Integrator: http://www.ncbi.nlm.nih.gov/gap/phegeni

Additional Information

Types of Sequence Variants:
https://online.science.psu.edu/biol011_sandbox_7239/node/7425

Nomenclature For The Description Of Sequence Variants By The Human Genome Variation Society (HGVS): 
http://www.hgvs.org/mutnomen/recs-DNA.html

Bioinformatics Program Main Page

Course Instructor: Dr. Medha Bhagwat (bhagwat@mail.nih.gov)