Variants that alter gene splicing are estimated to comprise up to a third of all disease-causing variants, yet they are hard to predict from DNA sequencing data alone. To overcome this, many groups are incorporating RNA-based analyses, which are resource intensive, particularly for diagnostic laboratories. There are thousands of functionally validated variants that induce mis-splicing; however, this information is not consolidated, and they are under-represented in ClinVar, which presents a barrier to variant interpretation and can result in duplication of validation efforts. To address this issue, we developed SpliceVarDB, an online database consolidating over 50,000 variants assayed for their effects on splicing in over 8,000 human genes. We evaluated over 500 published data sources and established a spliceogenicity scale to standardize, harmonize, and consolidate variant validation data generated by a range of experimental protocols. According to the strength of their supporting evidence, variants were classified as “splice-altering” (∼25%), “not splice-altering” (∼25%), and “low-frequency splice-altering” (∼50%), which correspond to weak or indeterminate evidence of spliceogenicity. Importantly, 55% of the splice-altering variants in SpliceVarDB are outside the canonical splice sites (5.6% are deep intronic). These variants can support the variant curation diagnostic pathway and can be used to provide the high-quality data necessary to develop more accurate in silico splicing predictors. The variants are accessible through an online platform, SpliceVarDB, with additional features for visualization, variant information, in silico predictions, and validation metrics. SpliceVarDB is a very large collection of splice-altering variants and is available at https://splicevardb.org.

中文翻译：

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SpliceVarDB：经过实验验证的人类剪接变体的综合数据库


据估计，改变基因剪接的变异占所有致病变异的三分之一，但仅从 DNA 测序数据中很难预测。为了克服这个问题，许多小组正在采用基于 RNA 的分析，这是资源密集型的，特别是对于诊断实验室。有数千种经过功能验证的变异会诱导错误剪接;但是，此信息并未合并，并且在 ClinVar 中的代表性不足，这为变体解释带来了障碍，并可能导致验证工作的重复。为了解决这个问题，我们开发了 SpliceVarDB，这是一个在线数据库，整合了 50,000 多个变异，分析了它们对 8,000 多个人类基因中剪接的影响。我们评估了 500 多个已发布的数据源，并建立了剪接性量表，以标准化、协调和整合由一系列实验方案生成的变异验证数据。根据其支持证据的强度，变体被分类为“剪接改变”（∼25%）、“不改变剪接”（∼25%）和“低频剪接改变”（∼50%），这与剪接发生的微弱或不确定的证据相对应。重要的是，SpliceVarDB 中 55% 的剪接改变变体位于规范剪接位点之外（5.6% 是深内含子）。这些变体可以支持变体管理诊断途径，并可用于提供开发更准确的计算机剪接预测因子所需的高质量数据。这些变体可通过在线平台 SpliceVarDB 访问，该平台具有可视化、变体信息、计算机预测和验证指标的附加功能。 SpliceVarDB 是一个非常大的拼接更改变体集合，可在 https://splicevardb.org 获取。