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functional variation

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  • 1. FANS Functional Analysis for Novel SNPs and Mutations Biomedical IT National Genotyping Center 05/29/09 http://fans.ngc.sinica.edu.tw
  • 2. What can FANS do for me?
    • If you have novel SNPs or point mutations, FANS will predict their functional effects before your assays.
    FANS Website
  • 3. What does FANS do?
    • Predict the Functional Effects of variations on Human and Mouse.
    • Classify the effects into 4 risk levels.
    • Prioritize the risks for variations.
    HIGH LOW 31347-A 50312+C 50940+G
  • 4. Functional Effects
    • Variation Location (NCBI RefSeq)
      • Coding Region / Splice-Site
    • Pre-mRNA Splicing (MIT, Burge Lab)
      • Exon Splicing Enhancer(238) / Silencer(279)
    • Amino Acid Change (Entrez Gene)
      • Stop Codon / Non-Synonymous
    • Protein Domain (NCBI Protein DB)
    • Protein Function (SIFT)
  • 5. Risk Analysis Flow VERY HIGHT VERY LOW RISK LEVEL HIGH MEDIUM No Splice-site? Yes Risk : High Splice site No SNPs in intron and untranslated region are not analyzed Non-synonymous? Risk : Very High Non-sense? Coding? Risk : High ESE or ESS Motif Diminished? Risk : Medium Non-sense Mis-sense (non-conservative change) Risk : High Mis-sense (protein domain abolished) Mis-sense (conservative change) Protein Structure Affection? ESE or ESS Motif Diminished? Protein Domain Abolished? Risk : High Splicing regulation (protein domain abolished) Protein Domain Abolished? Risk : Medium Splicing regulation Risk : Very Low Sense Variations in Transcripts Yes Yes Yes Yes Yes Yes Yes Yes No No No No No No No
  • 6. Input for FANS
    • Submitting a Variation
    • Species: Human or Mouse
    • Position: chromosome position
    • Strand: +, -
    • New Alleles: A, T, C, or G
  • 7. FANS Result
    • 1. Genome
    2. Gene 3. Transcript 4. Variation
  • 8. Part 1 : Overview
    • Overall variation info & risk level
    • Mouse-over a variation for more information, or click for details.
  • 9. Part 2 : Gene Structure
    • List Genes containing variations
    • Select a gene, and pick up a transcript to show the variations.
  • 10. Part 3 : Transcripts
    • Show variations in a transcript.
    • Click tabs to switch transcripts.
    • A variation in different transcripts may have different effects.
  • 11. Part 4 : Analysis Flow
  • 12. Risk Types & Risk Levels High Alters GT-AG splice site Splice site Non-coding Very Low Does not change amino acid and disrupt exon splicing regulation Sense Medium Disrupts exon splicing regulation, make the same protein domain Splicing regulation High Disrupts exon splicing regulation, make protein domain abolished Splicing regulation (protein domain abolished) Medium Does not change ESE, ESS and known protein domain and results in analogous protein structure Mis-sense (conservative change) High Changes ESE, ESS and known protein domain and results in protein structure abolished Mis-sense (protein domain abolished) High Predicts to affect protein structure Mis-sense (non-conservative change) Very High Causes premature stop codon and affects protein function Non-sense Coding Risk level Possible functional effect Risk type Coding type
  • 13. Performance A benchmarking test result of 10 variations analysis 1 47 Result pages 118 s 3968 s Time 170 Calculation 120 Fas-ESS 120 Rescue-ESE 100 SIFT 80 Ensembl 4 940 350 NCBI Steps FANS Manual
  • 14. Example
    • One point mutation on human chromosome 4 at position 1,775,917 causes a nucleotide change to cytosine.
    • Ans: chr4:1775917+C
  • 15. Achondroplasia ( 軟骨發育不全症 )
    • Achondroplasia is one of the most common causes of dwarfism. The appearance is of short stature with disproportionately short arms and legs and a large head.
    • Mutations involve the gene encoding fibroblast growth factor receptor 3 ( FGFR3 ), situated on chromosome 4. Most commonly, a point mutation causes the substitution of arginine for glycine ( G380R ) in the transmembrane region of the receptor.
  • 16. Acknowledgement
    • 緣起:陳志成老師、所長實驗室
    • 指導:姚文萱老師
    • 測試:蔡明芳
    • 支援: NGC, Biomedical IT
    • 經費: NRPGM
  • 17. Support
    • Online Help Document
    • http://fans.ngc.sinica.edu.tw
    • Bug Report / New Feature Request http://jira.ngc.sinica.edu.tw:8080/browse/GPE
    • Contact us
      • Tel: (02) 26523976 # 123 陳衍豪
      • Email: [email_address]
      • IBMS N801 - Biomedical IT
  • 18.
    • Thanks for listening
    • 歡迎提供意見與建議,讓我們可以做的更好 !
  • 19. References
    • Wang, Z., Rolish, M.E., Yeo, G., Tung, V., Mawson, M. and Burge, C.B. (2004) Systematic identification and analysis of exonic splicing silencers, Cell, 119, 831-845.
    • Ng, P.C. and Henikoff, S. (2003) SIFT : Predicting amino acid changes that affect protein function, Nucleic acids research, 31, 3812-3814.
    • Fairbrother, W.G., Yeo, G.W., Yeh, R., Goldstein, P., Mawson, M., Sharp, P.A. and Burge, C.B. (2004) RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons, Nucleic acids research, 32, W187-190.
    • Yuan, H.Y., Chiou, J.J., Tseng, W.H., Liu, C.H., Liu, C.K., Lin, Y.J., Wang, H.H., Yao, A., Chen, Y.T. and Hsu, C.N. (2006) FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization, Nucleic acids research, 34, W635-641.