As whole‐genome data become available for increasing numbers of individuals across diverse populations, the list of genomic variants of unknown significance (VOUS) continues to grow. One powerful tool in VOUS interpretation is determining whether an allele is too common to be considered pathogenic. As genetic and epidemiological parameters vary across disease models, so too does the pathogenic allele frequency threshold for each disease gene. One threshold‐setting approach is the maximum credible allele frequency (MCAF) method. However, estimating some of the input values MCAF requires, especially those involving heterogeneity, can present nontrivial statistical challenges. Here, we introduce FREQMAX, our alternative approach for determining allele frequency thresholds in carrier screening. FREQMAX makes efficient use of the data available for well‐studied traits and exhibits flexibility for traits where information may be less complete. For cystic fibrosis, more alleles are excluded as benign by FREQMAX than by MCAF. For less‐comprehensively characterized traits like ciliary dyskinesia and Smith–Lemli–Opitz syndrome, FREQMAX is able to set the allele frequency threshold without requiring a priori estimates of maximum genetic and allelic contributions. Furthermore, though we describe FREQMAX in the context of carrier screening, its classical population genetics framework also provides context for adaptation to other trait models.

中文翻译：

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FREQMAX 提供了一种在载体筛选中确定高分辨率等位基因频率阈值的替代方法

随着全基因组数据可用于不同人群中越来越多的个体，意义不明的基因组变异列表 (VOUS) 不断增加。VOUS 解释的一个强大工具是确定等位基因是否太常见而不能被认为是致病性的。由于遗传和流行病学参数因疾病模型而异，因此每个疾病基因的致病等位基因频率阈值也不同。一种阈值设置方法是最大可信等位基因频率 (MCAF) 方法。然而，估计 MCAF 需要的一些输入值，尤其是那些涉及异质性的输入值，可能会带来重大的统计挑战。在这里，我们介绍 FREQMAX，这是我们在载体筛选中确定等位基因频率阈值的替代方法。FREQMAX 有效地利用可用于已充分研究的特征的数据，并在信息可能不太完整的特征方面表现出灵活性。对于囊性纤维化，FREQMAX 比 MCAF 排除了更多的等位基因为良性。对于不太全面的特征，如纤毛运动障碍和 Smith-Lemli-Opitz 综合征，FREQMAX 能够设置等位基因频率阈值，而无需对最大遗传和等位基因贡献进行先验估计。此外，尽管我们在携带者筛选的背景下描述了 FREQMAX，但其经典的群体遗传学框架也为适应其他性状模型提供了背景。对于不太全面的特征，如纤毛运动障碍和 Smith-Lemli-Opitz 综合征，FREQMAX 能够设置等位基因频率阈值，而无需对最大遗传和等位基因贡献进行先验估计。此外，尽管我们在携带者筛选的背景下描述了 FREQMAX，但其经典的群体遗传学框架也为适应其他性状模型提供了背景。对于不太全面的特征，如纤毛运动障碍和 Smith-Lemli-Opitz 综合征，FREQMAX 能够设置等位基因频率阈值，而无需对最大遗传和等位基因贡献进行先验估计。此外，尽管我们在携带者筛选的背景下描述了 FREQMAX，但其经典的群体遗传学框架也为适应其他性状模型提供了背景。