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Table 2 Analyzed genes and variants with their involvement in blood-related functions and cancer

From: Driving mosaicism: somatic variants in reference population databases and effect on variant interpretation in rare genetic disease

Gene** AD condition Variant*** Variant type Allele count (< 35% of reads) COSMIC
ExAC gnomAD AA mutation Confirmed somatic No. of samples Samples being ‘hematopoietic and lymphoid’
ASXL1 * Bohring–Opitz syndrome NM_015338.5:c.1210C>T Nonsense 3 3 p.R404* Yes 10 90.0%
   NM_015338.5:c.2893C>T Nonsense 1 2 p.R965* Yes 17 70.6%
   NM_015338.5:c.1117C>T Nonsense 0 2
BRAF* Cardio-facio-cutaneous NM_004333.5:c.1799T>A Missense 1 2 p.V600E Yes 29,274 3.0%
  syndrome NM_004333.5:c.1406G>A Missense 1 0 p.G469E Yes 28 0.0%
CBL* Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia NM_005188.3:c.1186T>C Missense 1 0 p.C396R Yes 13 100.0%
   NM_005188.3:c.1259G>A Missense 2 2 p.R420Q Yes 27 77.8%
   NM_005188.3:c.1111T>C Missense 1 2 p.Y371H Yes 30 96.7%
DNMT3A* Tatton–Brown–Rahman syndrome NM_022552.5:c.2312G>A Missense 3 2 p.R771Q Yes 8 50.0%
   NM_022552.5:c.2644C>T Missense 4 3 p.R882C Yes 398 98.5%
   NM_022552.5:c.2536C>T Nonsense 1 0 p.Q846* No 1 100.0%
FGFR3▲∆ LADD syndrome/Thanatophoric dysplasia, type I NM_000142.5:c.1537G>A Missense 1 0
   NM_000142.5:c.746C>G Missense 1 0 p.S249C Yes 1,525 0.0%
IDH2* D-2-hydroxyglutaric aciduria 2 NM_001289910.1:c.263G>A Missense 4 3
KRAS* Noonan syndrome 3/RAS-associated autoimmune leukoproliferative disorder NM_004985.4:c.40G>A Missense 1 0 p.V14I Yes 34 14.71%
   NM_004985.4:c.35G>A Missense 1 1 p.G12D Yes 15,834 1.67%
PTPN11* Noonan syndrome 1 NM_002834.5:c.1471C>T Missense 1 NA
   NM_002834.5:c.794G>A Missense 1 0 p.R265Q Yes 4 100.0%
   NM_002834.5:c.188A>G Missense 0 1 p.Y63C No 4 100.0%
SETBP1 Schinzel–Giedion midface retraction syndrome NM_015559.3:c.2608G>A Missense 2 1 p.G870S Yes 72 98.61%
  1. A total of 16 variants (80.0% of variants reported here) residing in genes with good evidence of somatic mosaicism were also present in the Catalogue of Somatic Mutations in Cancer (COSMIC; info obtained on February 4, 2021). Across the genes, the variants were found in 1 to 29,274 samples. It is expected that the more frequent a mutation is in cancer samples, the higher the chance is that it is a driver mutation (the mechanism that makes those cells and the variants they carry more abundant in blood). A driver mutation is by definition a genetic change that gives an advantage to the cell. The advantage enables the cell to grow and proliferate better than other cells, which is a hallmark in cancer
  2. AA, amino acid; AD, autosomal dominant; ASXL1, ASXL transcriptional regulator 1; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CBL, Cbl proto-oncogene; COSMIC, Catalogue of Somatic Mutations in Cancer; DNMT3A, DNA methyltransferase 3 alpha; FGFR3, fibroblast growth factor receptor 3; IDH2, isocitrate dehydrogenase (NADP(+)) 2;; LADD, Lacrimo-auriculo-dento-digital; KRAS, KRAS proto-oncogene, GTPase; PTPN11, protein tyrosine phosphatase non-receptor type 11
  3. Evidence of somatic mosaicism involving the germline reported by Erickson [39] or Bedoukian et al.[30]
  4. Genes involved in stem cell and/or cell population proliferation
  5. Variant reported to affect or probably affect function based on Leiden Open Variation Database (LOVD; hg19/GRCh37) version 3.0 [40]
  6. *Genes with evidence of mosaicism that overlap with the list of 156 hematopoietic genes provided by Jaiswal et al. [13] in their Additional file 1: Table S2 (n = 7)
  7. **A gene shows good evidence of mosaicism when at least two alleles show signs of somatic origin (allelic imbalance)
  8. ***Rare disease- and/or cancer-related known pathogenic or likely pathogenic variants (in ClinVar and/or COSMIC)