Download - Church_NCBIvariation2013
![Page 1: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/1.jpg)
Deanna M. Church Staff Scientist, NCBI
@deannachurch
Variation Resources at NCBI
![Page 2: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/2.jpg)
Variation Resources Team at NCBIMing WardLon PhanBrad HolmesAnna GlodekMichael KholodovRama MaitiJuliana SampsonDavid ShaoEugene ShekhtmanQiang WangHua Zhang
Donna MaglottMelissa LandrumJennifer LeeGeorge RileyRay TullyCraig WallinShanmuga ChitipirallaDouglas HoffmanWonhee JangKen KatzMichael OvetskyRicardo Villamarin
Tim HefferonJohn LopezJohn GarnerChao Chen
Heidi Rehm, Harvard PartnersChrista Lese Martin, Geisinger Sherri Bale, GeneDxLisa Kalman, CDCBirgit Funke, Harvard PartnersMadhuri Hegde, Emory
Key Collaborators
![Page 3: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/3.jpg)
Figure credit: http://itknowledgeexchange.techtarget.com/
![Page 4: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/4.jpg)
dbSNPdbVar
ClinVarGTR
Quality ControlRef variantsReferences
Annotations
VisualizationTools
Data fromexternal sources
![Page 5: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/5.jpg)
Variant Definitions Variant Annotations
LocationEvidenceMethodology
PhenotypesConsequencesTestsOther Biology
dbSNPdbVar
ClinVarGTRdbSNP
![Page 6: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/6.jpg)
![Page 7: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/7.jpg)
GenBank RefSeq vs
Submitter Owned RefSeq Owned
Redundancy Non-RedundantUpdated rarely Curated
INSDC Not INSDC
BRCA183 genomic records31 mRNA records27 protein records
3 genomic records 5 mRNA records1 RNA record5 protein records
![Page 8: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/8.jpg)
Genome Res. 1999. 9: 677-679http://www.ncbi.nlm.nih.gov/snp
![Page 9: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/9.jpg)
![Page 10: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/10.jpg)
>gnl|dbSNP|ss76078129|allelePos=17|len=33|alleles='A/G’ GTGGCAGAGA CTGAATRAAGGGTTGAC CCAGGG
SNPs defined by flanking position
>gnl|dbSNP|ss3354770|allelePos=499|len=661|alleles='T/C’ actattcaca atagcaaaga cttggaacca acccaaatgt ccaacaatga tagactggat taagaaaatg tggcacatat acaccatgga atactaggca TTCCATTCTA CTGTGCACGA GTCACTGCAA ACTCAAGCAT TTCCAGAGTT CTGAAAGCTC AACTAAGAAC CAAGCCTACT CATTCAACAT CAACACACAC AGCACCCTGA GCGTCCAAAA CCACGGGGGT TATGTTCTAG ACCACAGGAC TGGCTACCTG GCCCTGCTCA AGGCGGCAGG ATCAATGGGC AAGAATGTGC AAGAATTTAC CACAACTCAG CCTTGCTGTG TCAACCACAG AGGCCAAGTA CCCCTAACAC CCAGATAGAG TAATTGTGCC TTACTTCTTT GTTCATTCCC ACCATTACAT TTTGTAAATT GGAACTTCTA GGAGGTTAGA AGGATATGCT GATCAAAAAA AGGGGACATA TTCAAGGAGT GTCCCTGGGT CAACCCTT Y ATTCAGTCTC TGCCACATGT CTAGTAACTG TGAGTGATGG GTGCATCAGT ATAATCCTGA GCCTCCCAAG GTACAGCCTT TCACTACTAT TCATCATATT GGCTAAGGTA TTCATCATAT TGGCTAAGGT ATTCACCAAC AGGGCTCATT TTCTATCAGA CC
![Page 11: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/11.jpg)
ss76078129 (aligns to plus strand)
'A/G’ ss76078129ss3354770 'T/C’
ss3354770 (aligns to minus strand)
ss76078129 (33bp)
ss76078129 (661bp)
![Page 12: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/12.jpg)
![Page 13: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/13.jpg)
rs397515413
![Page 14: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/14.jpg)
rs397515413
NC_000016.9 (chr16)
NW_003871055.3 (chr1 fix patch)
Hydin
Hydin2
![Page 15: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/15.jpg)
Defines variant by location rather than flanking sequence
VCF (Variant Call File)
![Page 16: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/16.jpg)
![Page 17: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/17.jpg)
Clustering microsatellites
![Page 18: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/18.jpg)
rs62645748
To be replacedby a Variation Viewer
To be replacedby a link to ClinVar
![Page 19: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/19.jpg)
rs62645748 (NCBI Homo sapiens annotation run 104)
![Page 20: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/20.jpg)
http://www.ncbi.nlm.nih.gov/dbvar
![Page 21: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/21.jpg)
Submitter Information
Study Information
Sample/Sampleset data
Experiment data
Variants
Contact and author information
Study meta-data (description, PMID, ProjectID, etc)
Sample IDs (if samples are consented)Sampleset ID for pooled samples (case v control sets)
Assay method (sequencing, array)Platform and analysis information
Variant definitions
![Page 22: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/22.jpg)
![Page 23: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/23.jpg)
Variant Call Ambiguitystart stop
Inner start Inner stop
Outer start Outer stop
Probes with decreased signal intensityProbes with expected signal intensity
breakpoint breakpoint
Inner start Inner stop
![Page 24: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/24.jpg)
Variant Call AmbiguityOuter start Outer stop
Fosmid clone (40 Kb +/- 1 Kb)
20Kb Clone has an insertionrelative to the genome
Clone has a deletionrelative to the genome 60 Kb
![Page 25: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/25.jpg)
![Page 26: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/26.jpg)
![Page 27: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/27.jpg)
http://www.ncbi.nlm.nih.gov/clinvar
![Page 28: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/28.jpg)
ClinVar data model and display
SCV
RCV
SCV
RCV
VariantPhenotypeSubmitter
AlleleVariant
Variant Phenotype
SCV SCV SCV SCV
![Page 29: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/29.jpg)
Allele summary• Gene• Variant type• Genomic location• HGVS expressions*• Molecular
consequence*• Links*• Frequency*
Phenotype summary• Names• Links*• Age of onset *• Prevalence *
Interpretation• Significance• Review status *• Accession.version *
* May be provided by NCBI
ClinVar RCV report - Overview
![Page 30: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/30.jpg)
ClinVar RCV report – Summary of assertions
• Each submission is accessioned and versioned• Terms provided by the submitter are mapped to controlled values• Method of review is clearly reported so primary data can be distinguished
from that reported in the literature
![Page 31: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/31.jpg)
ClinVar RCV report - Evidence
Under active review
![Page 32: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/32.jpg)
Allele report – available December
![Page 33: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/33.jpg)
http://www.ncbi.nlm.nih.gov/refseq/rsghttp://www.lrg-sequence.org/
![Page 34: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/34.jpg)
http://www.ncbi.nlm.nih.gov/refseq/rsg
RefSeq Gene
L R
![Page 35: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/35.jpg)
![Page 36: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/36.jpg)
http://www.ncbi.nlm.nih.gov/genome/tools/remap
From Assembly 1 <-> Assembly 2Assembly <-> RefSeqGene/LRGPrimary Assembly <-> Alternate loci
![Page 37: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/37.jpg)
1:215844373
![Page 38: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/38.jpg)
http://www.ncbi.nlm.nih.gov/variations/tools/reporter
This new look coming next month
![Page 39: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/39.jpg)
![Page 40: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/40.jpg)
http://www.ncbi.nlm.nih.gov/variation/view
![Page 41: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/41.jpg)
![Page 42: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/42.jpg)
http://www.ncbi.nlm.nih.gov/variation/tools/get-rm
Calls
Tests
cSRA
ConcordantDiscordantNA
Target audience: Clinical testing labsSubmissions from: Clinical and Research labs
![Page 43: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/43.jpg)
Twelve submitting labs to date
Twelve custom scripts to regularize data
Defined formats here:http://www.ncbi.nlm.nih.gov/projects/variation/get-rm
![Page 44: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/44.jpg)
Platforms
HiSeq 2000 HiSeq 2500 MiSeq Ion Torrent Sanger 4540
5
10
15
20
25
30
NA12878 Tests by Platform
![Page 45: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/45.jpg)
Lab Provided Validation
Variants validated in this sample using another platformVariants validated in another sample using another platformVariants seen in other samples from submitting lab using this platformVariants seen in public data setVariants that are novelVariants that were not assessed
![Page 46: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/46.jpg)
Based on May 2013 Data release
![Page 47: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/47.jpg)
Based on May 2013 Data release
![Page 48: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/48.jpg)
http://www.ncbi.nlm.nih.gov/variation/tools/get-rm
![Page 49: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/49.jpg)
![Page 50: Church_NCBIvariation2013](https://reader035.vdocuments.us/reader035/viewer/2022062514/5589cd28d8b42a302e8b45bb/html5/thumbnails/50.jpg)
Gene level concordance
Σ (max(xi)/Σ T)i = genotype callX = count per call for each variantT = total genotype calls per variant
Sums are taken over all variants ina gene.Tested regions taken into accountPhasing ignored