DEAFNESS VARIATION DATABASE


Examples - 13:20763071:T>C, 13:20763044, 13:20763045-20763071

What's new?

We are very excited to announce the release of DVD v8.2.1! With this release, we keep our list of genes consistent with the newest version of our OtoSCOPE® genetic testing platform. Coming Soon: update to all data sources that could impact classifications!

Version 8.2.1 changes

  • Expanded Variant List Filtering and Download Capabilities

    We have expanded the filtering capabilities for variant lists on the gene pages and variant search pages. Additionally, one filter or a set of filters can be applied simultaneously. Variant lists (filtered or unfiltered) may be downloaded in csv or json file formats. For more information on how to use these new features, please review our How to use this site page.

  • Gene Page Genome Browser

    Amongst many other functions, we have added the ability to add tracks to the Genome View corresponding to filtered variants from the Variant List table. Also, a VCF file can now be uploaded as a track into the Genome Browser. For more information, please review the Genome Browser Functionality section of our How to use this site page.

  • Interactive CADD Phred Score Box and Whisper Plots

    We have added the option to view an interactive CADD Phred score Box and Whisker Plot for pathogenicity classifications (Pathogenic, Likely pathogenic, VUS, Likely benign and Benign) for all variants in each gene. For more information, please review the CADD Phred Score Box and Whisker Plots section of our How to use this site page.

  • gnomAD v2.1.1 Annotations

    We now provide gnomAD v2.1.1 annotations as informative only data (i.e. not impacting classification). Future DVD releases will integrate gnomAD allele frequencies in the Kafeen algorithm for use in variant classification. For more information on gnomAD v2.1.1 vs v3, please see the gnomAD website.

  • Variant Classification

    Population-specific allele frequencies from Shearer AE, et al. Utilizing ethnic-specific differences in minor allele frequency to re-categorize reported pathogenic deafness variants. (aka. OtoSCOPE on variant pages) are no longer used for variant classification as richer and larger datasets are available in ExAC and gnomAD. The ethnic-specific allele frequencies from Shearer et al. 2014 remain available on variant pages for informational purposes.

  • Additional VEP Annotations

    We have expanded our use of VEP annotations to include information such as Interpro Domain and Motif data. For more information, please see the Variant Page and Variant Table sections of our How to use this site page.

  • More Efficient and Expanded Max MAF Organization on Variant Pages

    We have reorganized the way we display Max MAF population sources on Variant pages. Populations within each source are sorted with the greatest max MAF first. For sources with sub-population information, sub-population groups are sorted from top to bottom, greatest max MAF to least max MAF. Additionally, we provide homozygote alternate allele counts for sources that supply these data. For more information, please see the Variant Table sections of our How to use this site page.

Version 8.2 changes

  • VEP Annotations

    Ensembl's VEP has replaced ASAP for all variant annotations. This resolves descrepancies from ASAP's atypical InDel formatting as well as providing additional information for review on gene variant lists and on variant pages.

    For more information on VEP please see Ensembl's website.

    Note: We gather SIFT and PolyPhen-2 scores from both VEP and dbNSFP. In the event that both VEP and dbNSFP provide scores for a variant, VEP's SIFT and PolyPhen-2 scores override those of dbNSFP as a factor in our variant pathogenicity classification.

  • GnomAD Information Integration:

    GnomAD 2.0 variant frequencies are now available when viewing variant information. Please note that this data does not contribute to variant pathogenicity classifications and is provided for informational purposes only. GnomAD integration into pathogenicity classification is coming soon!

    Ashkenazi Jewish (ASJ) populations were excluded from MAF influenced variant classification.

  • CADD Information Integration:

    CADD phred score information is now available when viewing variant information. Please note that this data does not contribute to variant pathogenicity classifications and is provided for informational purposes only. CADD phred-like score integration into pathogencity classification is coming soon!

  • More variants have been manually-curated by the MORL
  • Variant Search Functionality

    There is now a variant search bar at the top of DVD webpages enabling the search of a specific variant, variants at a position, and/or variants in between a range of positions. The search bar is supported by an api interface as well. For more information about our api please see our API Documentation page. For more information about the search bar, please see our Help page.

  • Genome Browser

    A genome browser is now provided on gene pages for viewing gene level information in a track format.

    For more information regarding the genome browser plugin, please see BioDalliance's webpage.

  • Variant View Population Bolds and Highlights

    See the Population Maximum Minor Allele Frequencies (MAFs) and Their Sources section for more information.

  • Protein Structures via Force Field X (FFX)

    Protein structures are now provided on gene pages where available. These structures were modeled using Force Field X, an atomic resolution molecular modeling application.

    A promising source of evidence for classifying genetic variants is atomic resolution physics-based simulation techniques, which can test physical hypotheses about pathogenic mechanisms more rapidly and at a lower cost than many experimental approaches (e.g. model organisms). However, protein structural models (e.g. from X-ray crystallography, NMR, or homology modeling) required for simulation of hearing-related proteins are often based on imperfect experimental information (e.g. low-resolution diffraction) or may contain defects due to limited homology. We combine an advanced polarizable potential energy function, novel many-body optimization theory, and GPU-acceleration to locally and globally optimize all available deafness-associated protein models through the Force Field X (FFX) software program 1, 2, 3 . To objectively assess our models, we employed the MolProbity 4, 5 algorithm, which is widely used by crystallographers to aid refinement of models by reporting structural features that are known to be unphysical. Our optimization techniques improved the mean MolProbity score of 472 structures from 2.16 Å to 1.04 Å, consistent with protein structural models that approach atomic resolution.

    1. Tollefson, M. R. et al. (2018) OtoProtein: A Structural Database for Understanding Hearing Loss Genetics from GPU-Accelerated Polarizable Protein Side-Chain Repacking, In Progress.
    2. Fenn, T. D., and Schnieders, M. J. (2011) Polarizable atomic multipole X-ray refinement: Weighting schemes for macromolecular diffraction, Acta Crystallogr. D 67, 957-965.
    3. LuCore, S. D., Litman, J. M., Powers, K. T., Lynn, A. M., Gao, S., Tollefson, W. T. A., Fenn, T. D., Washington, M. T., and Schnieders, M. J. (2015) Dead-End Elimination for Many-Body Potentials Repacks Low-Resolution X-ray Diffraction Models into Atomic Resolution Structures, Proc. Natl. Acad. Sci. U.S.A.
    4. Chen, V.B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallographica Section D-Biological Crystallography 66, 12-21 (2010).
    5. Davis, I.W. et al. MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Research 35, W375-W383 (2007).

    For information on the structure viewer plugin, please see NGL Viewer's github.

Version 8.1 changes

  • Four genes have been renamed to match HUGO-approved gene symbols: ADGRV1 (GPR98), WHRN (DNB31), PJVK (DFNB59), TWNK (C10orf2)
  • More variants have been manually-curated by the MORL

Version 8.0 changes

  • Genes added: ATP6V1B1, CD164, CDC14A, EPS8L2, FGF3, FGFR1, FGFR2, GATA3, KITLG, LOXL3, MCM2, MET, PEX1, PEX6, ROR1, S1PR2, TBX1
  • More variants have been manually-curated by the MORL
  • A new downloadable version of the DVD is now available here

Version 7.0 changes

  • Genes added: C10orf2, CISD2, COL4A3, COL4A4, COL4A5, COL4A6, DCDC2, EDN3, EDNRB, FAM65B, MITF, MT-TL1, MT-TS1, NARS2, NLRP3, OPA1, OSBPL2, PAX3, POLR1C, POLR1D, SLITRK6, SNAI2, SOX10, TCOF1, TECTB, TMEM132E
  • Genes removed: CATSPER2, CRYL1, GTPBP3, MIR182, MIR183, MTO1, TFB1M, TRMU
  • Minor allele frequencies from ExAC are now included
  • Minor allele frequencies from 1000 Genomes have been updated from Phase 1 to Phase 3
  • ClinVar annotations have been updated to the March 1, 2016 release
  • dbSNP rs IDs have been updated from Build 142 to Build 146
  • Prediction data have been updated from dbNSFP v2.1 to dbNSFP v3.0
  • A downloadable version of the DVD is now available here
  • More data from our in-house OtoDB have been curated and added
  • We have added more information on variant classifications and the nomenclature we use for the DVD