Table 3.
Candidate inclusions to BMF/HM predisposition gene lists.
| Gene symbol |
Canonical Transcript Coding size (aa) |
TF Family | Human phenotype | Constraint | gnomAD No. of LOF (different/ total) |
COSMIC | Murine embryonic lethality | Malignant Fusions | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phenotype | Zygosity | LOEUF | pLI score | Domain | Average domain constraint | point mutations in Hematopoietic tissue/total samples (%) |
No. of LOF | Het | Hom | Somatic | HM specific | ||||
| ETV2 | 342 | ETS | None reported | N/A | 1.42 | 0 | ETS | 0.5563, SI | 28/121 | 7/5924 (0.12%) | 10/155 (6.45%) | No | Yes | None observed | None observed |
| ELF1 | 501 | ETS | None reported | N/A | 0.58 | 0.01 | ETS | 0.4664, I | 17/19 | 53/8011 (0.66%) | 39/659 (4.7%) | No | No | None observed | None observed |
| FEV | 238 | ETS | None reported | N/A | 1.32 | 0.01 | ETS | 0.3402, I | 5/7 | 4/5924 (0.07%) | 4/99 (4.0%) | No | No | FEV/EWS | None observed |
| ETS1 | 485 | ETS | None reported | N/A | 0.39 | 0.78 | ETS | 0.221, I | 7/7 | 136/6148 (2.21%) | 32/1086 (2.9%) | No | No | None observed | None observed |
| ETS2 | 469 | ETS | None reported | N/A | 0.2 | 1 | ETS | 0.23, I | 5/8 | 22/5924 (0.37%) | 17/401 (4.2%) | No | Yes | None observed | None observed |
| IKZF2 | 526 | IKAROS | None reported | N/A | 0.29 | 0.99 | ZF | 0.22, I | 6/157 | 71/6587 (1.08%) | 35/1124 (3.11%) | No | No | None observed | None observed |
| IKZF4 | 585 | IKAROS | None reported | N/A | 0.38 | 0.9 | ZF | 0.11, HI | 9/11 | 20/5924 (0.34%) | 13/423 (3.07%) | No | No | None observed | None observed |
| GFI1B | 330 | Proto-oncogene | Bleeding disorder, platelet-type, 17* | AD, AR | 0.86 | 0 | ZF ZF ZF ZF |
0.53, SI 0.51, I 0.34, I 0.7241, N |
16/52 | 28/5924 (0.47%) | 11/500 (2.2%) | No | Yes | None observed | None observed |
|
TAL1
(SCL) |
331 | bHLH | Leukemia, T-cell acute lymphocytic | Somatic | 0.7 | 0.57 | BHLH | 0.35, I | 10/47 | 19/6120 (0.31%) | 34/398 (8.54%) | No | Yes | None observed | None observed |
| LYL1 | 280 | bHLH | Leukemia, T-cell acute lymphoblastoid | Not recorded | 0.61 | 0.77 | BHLH | 0.50, I | 3/4 | 7/5924 (0.12%) | 8/127 (6.3%) | No | No | None observed | None observed |
| LMO2 | 227 | bHLH | Leukemia, acute T-cell | Not recorded | 1.028 | 0.16 | LIM 1 LIM 2 |
0.54, SI 0.391, I |
9/13 | 31/6037 (0.51%) | 6/358 (1.68%) | No | Yes | None observed | None observed |
| MEIS1 | 390 | Homeo-box | None reported | N/A | 0.14 | 1 | MEIS Homeo-box |
0.19, I 0.045, HI |
2/2 | 102/5924 (1.72%) | 18/1094 (1.65%) | No | Yes | None observed | None observed |
| TCF12 | 706 | bHLH | Craniosynostosis 3, Hypogonadotropic hypogonadism 26 with/without anosmia | AD, AR | 0.37 | 0.68 | Helix-loop-Helix DNA BD | 0.2837, I | 24/29 | 113/6172 (1.83%) | 67/1550 (4.3%) | No | Postnatal lethality within two weeks | TCF12/NR4A3 | None observed |
| GFI1 | 422 | Proto-oncogene | Neutropenia, severe congenital 2* | AD | 0.56 | 0.25 | ZF 1 ZF 2 ZF 3 |
0.2678, I 0.6286, SI 0.6491, SI |
11/13 | 15/6073 (0.25%) | 20/308 (6.5%) | No | No | None observed | None observed |
| FOS | 380 | FOS | None reported | N/A | 0.65 | 0.26 | bZIP TF | 0.3376, I | 6/6 | 8/5924 (0.14%) | 16/211 (7.6%) | No | No | None observed | None observed |
| HOXA9 | 272 | Homeo-box | None reported | N/A | 1.62 | 0 | Homeo-box Domain | 0.4315, I | 13/41 | 14/6233 (0.22%) | 5 (2.33%) | No | No | None observed | HOXA9/NUP98, HOXA9/MSI2 |
| FOSB | 338 | FOS | None reported | N/A | 0.3 | 0.98 | bZIP TF | 0.16, HI | 6/6 | 9/5924 (0.15%) | 11 (3.45%) | No | No | None observed | None observed |
| FOXC2 | 501 | Forkhead box | Lymphedema-distichiasis syndrome with renal disease and diabetes mellitus | AD | 0.79 | 0.13 | Forkhead Domain | 0.21, I | 6/7 | 3/5924 (0.05%) | 5 (1.66%) | No | Yes | None observed | None observed |
| EKLF (KLF1) | 362 | KLF | [Hereditary persistence of fetal hemoglobin], Dyserythropoietic anemia, congenital, type IV, Blood group–Lutheran inhibitor, - Ineffective erythropoiesis | AD | 1.13 | 0 | ZF | 0.83, N | 16/34 | 5/5924 (0.1%) | 2 (1%) | No | Yes | None observed | None observed |
| NFKB1 | 969 | NF-kappaB | Immunodeficiency, common variable, 12, | AD | 0.16 | 1 | Ankyrin repeat 1, Ankyrin Repeat 2, Death Domain |
0.52, I 0.57, SI 0.63, SI |
10/82 | 67/6967 (0.96%) | 18 (1.98%) | No | No | None observed | |
*GFI1 (S36N) polymorphism is associated with incidence and/or prognosis of AML, MDS and multiple myeloma (32).
Candidate inclusions to BMF/HM predisposition gene lists, not found in high evidence Genomics England PanelApp panels: Hematological malignancies cancer susceptibility [Version 3.3] and/or Bleeding and Platelet Disorders [Version 1.16] + Cytopenias and congenital anemias [Version 1.111]. TFs are isolated by involvement in hematopoiesis, oncogenic potential, and previous disease association. Human phenotype is collated through OMIM. Slightly intolerant, SI; intolerant, I; highly intolerant, HI; neutral, N; loss-of-function observed over expected upper bound fraction, LOUEF.
NA, not applicable.