Table 2 Literature review on the identified putative somatic missense variants in the hematological malignancy cohorts.
Patient ID | Cluster | Diagnosis | Variant | Cohort freq1 | Public freq2 | Proximal functional site | Methods | Function/mutant consequence/mutant phenotype | Reference | Organism |
|---|---|---|---|---|---|---|---|---|---|---|
P6 | NA | MDS | Y55H | 1/756; 0.0013 | 0 | S56F | mutagenesis | temperature-sensitive partial loss of function | Poulter [7] | human |
R57 | structural | ATP-contacting residue (gamma phosphate) | Lv [20] | human | ||||||
R57K/A | mutagenesis | significantly reduced nitrate reductase activity in R515 (R73 in E. Coli) double mutants | Lake [40] | E. Coli (R14K/A) | ||||||
P33 | NA | B-ALL | D103N | 1/321; 0.0031 | 0 | S140 | structural | SCCH/IAD/AAD interacting residue; substitution has minimal effect on thioester bond formation | Hann [41] | S. Pombe (Q105A) |
P40 | NA | T-NHL | I123T | 1/148; 0.0068 | 0 | S140 | structural | SCCH/IAD/AAD interacting residue; substitution has minimal effect on thioester bond formation | Hann [41] | S. Pombe (Q105A) |
P7 | NA | MDS | R182H | 1/756; 0.0013 | gnomAD (3/165293; 1.81e-5) | A189T* | mutagenesis | slightly less efficient ubiquitination, higher apoptotic rate than wild type | Lao [42] | mouse (A189T) |
P8 | ATP-binding | MDS + T-NHL | A478S | 1/756; 0.0013 | 0 | A478 | structural | ATP-contacting residue (alpha phosphate); consists the oxyanion hole and GxGxxG ATP binding motif | Lv [20] | human |
P37 | ATP-binding | B-NHL (FL) | V524D | 1/541; 0.0018 | 0 | K528N* | mutagenesis | mutant tissue apoptotic and enlarged wild type tissue (total loss of function) | Pfleger [39] | Drosophila(K663N) |
K528A | structural; mutagenesis | ATP-contacting residue (beta phosphate); ATP binding attenuated and reduced Ub-adenylation | Tokgöz [43] | human | ||||||
P39 | ATP-binding | B-NHL (HCL) | R551C | 1/541; 0.0018 | 0 | N550* | mutagenesis | 3-fold decrease in thioester bond formation | Hann [41] | S. Pombe (E511R) |
R551 | structural | ATP-contacting residue | Lv [20] | human | ||||||
P9 | Ub Interface III | CML + MPN | E597A | 1/500; 0.0020 | 0 | C588Y* | mutagenesis | mutant tissue apoptotic and enlarged wild type tissue (total loss of function) | Pfleger [39] | Drosophila (C723Y) |
G599 | structural | ubiquitin-contacting residue | Lv [20] | human | ||||||
case | Ub Interface III | MDS | N606I | 1/756; 0.0013 | 0 | N606 | structural | van der Waals contacts with Ub | Lv [20] | human |
P10 | Ub Interface III | MDS | S621C | 1/756; 0.0013 | COSMIC MDS-RS (1/9; 0.11) | S621 | structural | hydrogen bond with Ub | Lv [20] | human |
S621C | sequencing | somatic variant identified in a SF3B1-mut MDS patient (COSMIC-cited) | Papaemmanuil [44] | human | ||||||
S621C | sequencing | somatic variant identified in a patient with vasculitis | Beck [36] | human | ||||||
P36 | Interdomain Interface | B-NHL (FL) | R747C | 1/541; 0.0018 | COSMIC colorectal carcinoma (1/619; 0.0016) | R747E* | mutagenesis | 4-fold decrease in thioester bond formation | Hann [41] | S. Pomne (R707E) |
R747 | structural | salt bridge between E252 of the FCCH domain | Lv [20] | human | ||||||
P747C | sequencing | somatic variant identified in a female patient with large intestine adenocarcinoma (COSMIC-cited) | Giannakis () | human | ||||||
P11 | Interdomain Interface | MDS | P749L | 1/756; 0.0013 | 0 | P749L* | mutagenesis | enlarged mutant tissue (temperature-sensitive partial loss of function) | Drosophila (P884L) | |
P38 | Ub Interface III | B-NHL (FL) | I890T | 1/541; 0.0018 | 0 | I891 | structural | van der Waals contacts with Ub | Lv [20] | human |
P6 | Ub Interface III | MDS | I894F | 1/756; 0.0013 | 0 | I891 | structural | van der Waals contacts with Ub | Lv [20] | human |
case | Ub Interface III | MDS | I894S | 1/756; 0.0013 | 0 | I891 | structural | van der Waals contacts with Ub | Lv [20] | human |
P12 | NA | MDS | P1014L/splice | 1/756; 0.0013 | 0 | R1010 | structural | E2 enzyme (Ubc4) contact site | Olsen [45] | S. Pombe (R965) |
del(923-1058) | mutagenesis | IRF3 binding lost | Chen [46] | human/zebrafish |
