Structural analysis of TERT rare variants. (A) Human TERT homology model. The ring, formed by the TRBD, RTD, and CTE domain, is colored in purple and the TEN domain in green. Panels B, C, D, and E show the TERT rare variants within the RTD (enzymatic core and IFD regions), TRBD, TEN, and CTE domains (including the FVYL pocket), respectively. R622 belongs to the RTD but is displayed in panel C because of its proximity to the TRBD. The side-chains for the residues mutated in the MDS rare variants (crimson carbon atoms) and the catalytic residues in the active site (yellow carbon atoms) are shown in stick representation. The modeled regions of TERC are in orange, whereas the DNA substrate is depicted in black.