Investigation of the transcriptional impact of rare germline JAK/STAT variants found in a Tyrolean alpine community.

The impact of most missense variants in immune regulatory genes on steady-state immune transcriptome expression in healthy individuals in real-world conditions remains largely unexplored. Here, we investigated the transcriptional impact of 21 germline variants in JAK, TYK2, and STAT family genes identified within a healthy Austrian alpine cohort. Of the 98 participants 35 carried only one variant and 32 carried two or more variants. Allele frequencies (AF) of these germline mutations, based on the gnomAD and All of Us databases, ranged from approximately 10- 6 for three very rare variants to approximately 10- 1 for the most common. In silico prediction tools combined with surveying COSMIC and the NIH ClinVar databases were used to explore links with known disease. Thirteen of the 21 variants were reported in the COSMIC database, suggesting gain-of-function activity. Structural analysis revealed clear mechanistic basis for few variants, although some appeared to have modest structural effects in agreement with their weak GOF phenotypes.