Table 1.
Summary and pathogenicity predictions of 28 unique CSF3R variants found on OncoPlus testing of blood or bone marrow from patients with hematologic malignancies
| CSF3R variant | rs n | Located in COSMIC (v90) | Population allele frequency (gnomAD total) | OncoPlus cohort allele frequency | REVEL score | Damaging in silico predictions | Benign in silico predictions | ClinVar classification | ACMG classification | Known germ line variant | Cohort germ line status |
|---|---|---|---|---|---|---|---|---|---|---|---|
| p.Trp547* c.1640G>A | rs138156467 | Yes: CMML ×1 | 0.0002665 | 0.0008143 | NA | DANN, FATHMM-MKL, LRT, and MutationTaster | FATHMM-XF | Pathogenic | Pathogenic: PVS1, PM3, PP3 | Yes | Germ line |
| p.Gln739* c.2215C>T | NA | Yes: AML ×2 | NF | 0.0008143 | NA | DANN, FATHMM-MKL, and MutationTaster | FATHMM-XF and LRT | Not reported | Pathogenic: PVS1, PM2, PP3 | No | Somatic |
| p.Thr618Ile c.1853C>T | rs796065343 | Yes: AML ×13, CNL ×13, CMML ×3, CML ×3, ALL ×2 | NF | 0.0016287 | 0.412 | DANN, DEOGEN2, FATHMM-MKL, FATHMM-XF, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | FATHMM | Pathogenic/likely pathogenic | Pathogenic: PS3, PM2, PM6, PP1, PP3 | No | Somatic |
| p.Ser469Alafs*22 c.1404del | rs769210858 | Yes: SCC ×1, biliary ×2, breast ×1, endometrium ×1, colorectal ×11, gastric ×2 | NF | NA | NA | NA | NA | Not reported | Likely pathogenic: PVS1, PM2 | No | Somatic |
| p.Ser783Glnfs*6 c.2346dupC | NA | Yes: CNL ×2, AML ×4 | NF | NA | NA | NA | NA | Not reported | Likely pathogenic: PVS1, PM2 | No | Somatic |
| p.Arg308Cys c.922C>T | rs606231473 | Yes: colorectal ×1 | NF | 0.0008143 | 0.807 | DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, and SIFT | None | Pathogenic | Likely pathogenic: PS3, PM2, PP3 | Yes | Somatic |
| p.Pro784Thr c.2350C>A | NA | No | NF | 0.0008143 | 0.43 | FATHMM, FATHMM-MKL, FATHMM-XF, M-CAP, MutationAssessor, MutationTaster, PROVEAN, and SIFT | DANN, DEOGEN2, LRT, PrimateAI, and SIFT4G | Not reported | Uncertain significance*: PM2, PP3 | No | Germ line |
| p.Ala119Thr c.355G>A | rs142999683 | No | 0.0006339 | 0.0008143 | 0.491 | DANN, FATHMM, FATHMM-MKL, FATHMM-XF, LRT, M-CAP, MutationAssessor, MutationTaster, SIFT and SIFT4G | DEOGEN2, PROVEAN and PrimateAI | Uncertain significance | Uncertain significance*: PP3 | Yes | Germ line |
| p.Thr486Met c.1457C>T | rs759506026 | No | 0.0001096 | 0.0008143 | 0.091 | DANN, M-CAP, MutationAssessor, and SIFT4G | DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, MutationTaster, PROVEAN, PrimateAI, and SIFT | Not reported | Uncertain significance: BP4 | No | Germ line |
| p.Thr420Ala c.1258A>G | rs1479865089 | No | 0.00000398 | 0.0008143 | 0.022 | FATHMM-MKL, SIFT, and SIFT4G | DANN, DEOGEN2, FATHMM, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, and PrimateAI | Not reported | Uncertain significance: PM2, BP4 | No | Germ line |
| p.Thr640Ile c.1919C>T | rs121918426 | No | 0.0004813 | 0.0008143 | 0.118 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Conflicting interpretations of pathogenicity: likely benign (1), uncertain significance (1) | Uncertain significance: PM5, BP4 | Yes | Germ line |
| p.Asp681His c.2041G>C | NA | No | NF | NA | 0.09 | DANN, FATHMM-MKL, FATHMM-XF, PrimateAI, SIFT, and SIFT4G | DEOGEN2, FATHMM, LRT, M-CAP, MutationAssessor, MutationTaster, and PROVEAN | Not reported | Uncertain significance: PM2 | No | Somatic |
| p.Lys49Arg c.146A>G | rs766274573 | No | 0.00003582 | 0.0008143 | 0.2 | FATHMM and M-CAP | DANN, DEOGEN2, FATHMM-MKL, FATHMM-XF, GERP, LRT, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.His94Arg c.281A>G | rs374695394 | No | 0.00001061 | 0.0008143 | 0.166 | M-CAP | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.Val812Ile c.2434G>A | rs528303671 | No | 0.00000803 | 0.0008143 | 0.104 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.Ala603Ser c.1807G>T | rs765606679 | No | 0.00001988 | 0.0008143 | 0.072 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.Gln216His c.648A>C | rs747021516 | No | 0.00008491 | NA | 0.02 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.Pro803Ser c.2407C>T | rs35622214 | No | 0.0005376 | 0.0024430 | 0.027 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.Arg698Cys c.2092C>T (NM_156039.3) | rs3918021 | No | 0.002246 | 0.0016287 | 0.08 | DANN and SIFT | FATHMM, FATHMM-MKL, LRT, M-CAP, MutationTaster, PROVEAN, and SIFT4G | Not reported | Uncertain significance: BP4 | No | Unconfirmed |
| p.Arg583His c.1748G>A | rs148104401 | No | 0.000559 | 0.0008143 | 0.045 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Conflicting interpretations of pathogenicity: Likely benign (1), uncertain significance (1) | Likely benign: BP4, BP6 | Yes | Germ line |
| p.Arg583Cys c.1747C>T | rs3917997 | No | 0.0001274 | 0.0008143 | 0.177 | DANN, M-CAP, PROVEAN, SIFT, and SIFT4G | DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, MutationAssessor, MutationTaster, and PrimateAI | Uncertain significance | Likely benign: BP4, BP6 | Yes | Germ line |
| p.Glu808Lys c.2422G>A | rs146617729 | Yes: CMML ×2, MDS ×2, AML ×1 | 0.006396 | 0.0105863 | 0.086 | DANN, MutationAssessor, MutationTaster, SIFT, and SIFT4G | DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, LRT, PROVEAN, and PrimateAI | Benign/likely benign | Likely benign: BS2, BP6 | Yes | Germ line |
| p.Arg440Gln c.1319G>A | rs3918020 | No | 0.003326 | 0.0048860 | 0.017 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Likely benign | Likely benign: BS2, BP4, BP6 | Yes | Germ line |
| p.Leu619Ser c.1856T>C | rs141619366 | No | 0.0003288 | 0.0008143 | 0.149 | DANN, M-CAP, MutationAssessor, SIFT, and SIFT4G | DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, LRT, MutationTaster, PROVEAN, and PrimateAI | Likely benign | Likely benign: BP4, BP6 | Yes | Germ line |
| p.Met696Thr c.2087T>C (NM_156039.3) | rs148916169 | Yes: CMML ×3 | 0.006198 | NA | 0.008 | None | DANN, FATHMM, FATHMM-MKL, GERP, MutationTaster, PROVEAN, SIFT, and SIFT4G | Not reported | Likely benign: BS2, BP4 | No | Unconfirmed |
| p.Glu149Asp c.447G>C | rs139332126 | No | 0.002931 | 0.0057003 | 0.015 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, M-CAP, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Benign/likely benign | Likely benign: BP4, BP6 | Yes | Germ line |
| p.Asp320Asn c.958G>A | rs3918018 | No | 0.01893 | NA | 0.091 | None | DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, GERP, LRT, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Benign | Benign: BS1, BS2, BP4, BP6 | Yes | Germ line |
| p.Glu405Lys c.1213G>A | rs3918019 | No | 0.005387 | 0.0032573 | 0.037 | DANN | DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, LRT, MutationAssessor, MutationTaster, PROVEAN, PrimateAI, SIFT, and SIFT4G | Benign | Benign: BS1, BS2, BP4, BP6 | Yes | Germ line |
Table lists all unique CSF3R variants identified (transcript NM_000760.3 unless otherwise indicated), including those from cases outside the original OncoPlus testing cohort. OncoPlus cohort allele frequency was determined only for variants found within the initial 632 patient cohort who underwent OncoPlus testing from June 2017 through October 2019.
ACMG, American College of Medical Genetics and Genomics; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; NA, not applicable; NF, not found; SCC, squamous cell carcinoma.
*
Germ line VUSs that met preset criteria for inclusion in functional testing, including: total population variant frequency <0.001 in gnomAD (v2.1.1), REVEL score ≥0.4, and greater number of damaging compared with benign in silico functional predictions.