To reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole‐exome sequencing data set comprised of 1686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B, and THBS4 genes. We reported 36 clinically relevant variants (submitted as pathogenic, risk factors, or drug response in ClinVar) with significant frequency differences between Italy and Europe. We then explored putatively pathogenic variants in the Italian exome. On average, our Italian individuals carried 16.6 protein‐truncating variants (PTVs), with 2.5% of the population having a PTV in one of the 59 American College of Medical Genetics (ACMG) actionable genes. Lastly, we looked for PTVs that are likely to cause Mendelian diseases. We found four heterozygous PTVs in haploinsufficient genes (KAT6A, PTCH1, and STXBP1) and three homozygous PTVs in genes causing recessive diseases (DPYD, FLG, and PYGM). Comparing frequencies from our data set to other public databases, like gnomAD, we showed the importance of population‐specific databases for a more accurate assessment of variant pathogenicity. For this reason, we made aggregated frequencies from our data set publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it; NIG‐ExIT).

中文翻译：

---

1686 个意大利外显子组遗传结构的功能和临床意义

为了重建意大利基因结构的表型和临床意义，我们彻底分析了由 1686 名健康意大利人组成的全外显子组测序数据集。我们在HERC2、OR52R1、ADH1B和THBS4中发现了 6 个以前未报道过的变异，在意大利北部和南部之间具有显着的频率差异基因。我们报告了 36 个临床相关变异（在 ClinVar 中作为致病、风险因素或药物反应提交），在意大利和欧洲之间具有显着的频率差异。然后，我们探索了意大利外显子组中假定的致病变异。平均而言，我们的意大利个体携带 16.6 个蛋白质截短变体 (PTV)，其中 2.5% 的人口在 59 个美国医学遗传学会 (ACMG) 可操作基因之一中具有 PTV。最后，我们寻找可能导致孟德尔疾病的 PTV。我们在单倍体不足基因（KAT6A、PTCH1和STXBP1）中发现了四个杂合 PTV，在导致隐性疾病的基因（DPYD、FLG和PYGM ）中发现了三个纯合 PTV）。将我们数据集的频率与其他公共数据库（如 gnomAD）进行比较，我们展示了特定人群数据库对于更准确地评估变异致病性的重要性。出于这个原因，我们公开了来自我们数据集的汇总频率，作为临床医生和研究人员的工具（http://nigdb.cineca.it；NIG-ExIT）。