MECOM variations in patients with hypomegakaryocytic thrombocytopenia
| Patient . | Genomic (GRCh38.p7) variation (refSNP) . | Transcript variant 3 (NM_001105078.3) . | PROVEAN14 prediction/score (cutoff −2.5) . | SIFT15 prediction/score (cutoff 0.05) . | PolyPhen-216 prediction/score . | MutationTaster17 prediction/probability . | Found in ExAC or 1000G (MAF/MAC) . | Pathogenicity (ACMG Consensus12,13 ) . | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| E/I No. . | CDS/protein . | Type . | ||||||||||
| P1 | chr3:g.169100919G>A | E11 | c.2251C>T p.His751Tyr | Missense | Deleterious −5.48 | Damaging 0.000 | Probably damaging 1.000 | Disease causing 1.000 | N | Likely pathogenic | ||
| P2 | chr3:g.169100894T>A | E11 | c.2276A>T p.Gln759Leu | Missense | Deleterious −6.27 | Damaging 0.001 | Probably damaging 0.996 | Disease causing 1.000 | N | Likely pathogenic | ||
| P3 | chr3:g.169100892G>A | E11 | c.2278C>T p.Pro760Ser | Missense | Deleterious −6.97 | Damaging 0.006 | Probably damaging 1.000 | Disease causing 1.000 | N | Likely pathogenic | ||
| P4 | Chr3:g.169100962_ 169100963delTC | E11 | c.2208-1_2208delGA p.Arg736Ser fs*13 | Deletion frameshift | NA | NA | NA | Disease causing 1.000 | N | Pathogenic | ||
| P5/P6 | chr3:g.169100922G>A (rs864309724) | E11 | c.2248C>T p.Arg750Trp | Missense | Deleterious −6.98 | Damaging 0.000 | Probably damaging 1.000 | Disease causing 1.000 | N | Pathogenic | ||
| P7 | chr3:g.169093016G>A | E13 | c.2542C>T p.Arg848Ter | Nonsense | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P8 | chr3:g.169128041G>T | E4 | c.69C>A p.Cys23Ter | Nonsense | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P9 | chr3:g.169095075C>G | I12 | c.2455+1G>C Loss of splice site | Splice site mutation | NA | NA | NA | Disease causing 1.000 | N | Pathogenic | ||
| P10 | chr3:g.169116194G>A | E7 | c.1114C>T p.Gln372Ter | Nonsense | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P11 | Chr3:g.169095111_ 169095112insT | E12 | c.2419_2420insAp.Arg807Lys fs*7 | Insertion frameshift | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P12 | chr3:g.169095235A>G | E12 | c.2296T>C p.Cys766Arg | Missense | Deleterious −10.12 | Damaging 0.000 | Possibly damaging 0.845 | Disease causing 1.000 | N | Likely pathogenic | ||
| P13 | chr3:g.169116402G>C | E7 | c.906C>G p.Ser302Arg | Missense | Neutral −1.53 | Tolerated 0.071 | Probably damaging 0.999 | Disease causing 1.000 | N | Uncertain significance | ||
| P14/P15 | chr3:g.169095082T>C (rs200049869) | E12 | c.2449A>G p.Met817Val | Missense | Neutral 0.16 | Tolerated 0.706 | Benign 0.000 | Disease causing 0.949 | ExAc: Y (0.0004/45) 1000G: N | Uncertain significance | ||
| P16/P17/ P18 | chr3:g.169143748C>A (rs116535717) | E2 | c.-105G>T?c | 5′UTR | NA | NA | NA | Disease causing 0.529 | ExAc: Y (0.0047/561) 1000G: Y (0.0068/34) | Benign | ||
| P19 | chr3:g.169122674T>C (rs34896995) | E5 | c.320A>G p.Gln107Arg | Missense | Neutral −2.26 | Damaging 0.030 | Possibly damaging 0.946 | Disease causing 1.000 | ExAc: (0.0026/319) 1000G: (0.0010/5) | Uncertain significance | ||
| P20 | chr3:g.169145034T>C (rs370795924) | 5′UTR | 5′UTR | NA | NA | NA | Disease causing 1.000 | N (1 individual48 ) | Uncertain significance | |||
| P16/P17/ P18TF1-1 | chr3:g.169143748C>A (rs116535717) | E3* | c.88G>T p.Ala30Ser* | Missense* | Neutral −1.11 | Damaging 0.003 | Possibly damaging 0.548 | Disease causing 0.529 ExAc: 561/120542 1000G: 34 | Benign | |||
| Patient . | Genomic (GRCh38.p7) variation (refSNP) . | Transcript variant 3 (NM_001105078.3) . | PROVEAN14 prediction/score (cutoff −2.5) . | SIFT15 prediction/score (cutoff 0.05) . | PolyPhen-216 prediction/score . | MutationTaster17 prediction/probability . | Found in ExAC or 1000G (MAF/MAC) . | Pathogenicity (ACMG Consensus12,13 ) . | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| E/I No. . | CDS/protein . | Type . | ||||||||||
| P1 | chr3:g.169100919G>A | E11 | c.2251C>T p.His751Tyr | Missense | Deleterious −5.48 | Damaging 0.000 | Probably damaging 1.000 | Disease causing 1.000 | N | Likely pathogenic | ||
| P2 | chr3:g.169100894T>A | E11 | c.2276A>T p.Gln759Leu | Missense | Deleterious −6.27 | Damaging 0.001 | Probably damaging 0.996 | Disease causing 1.000 | N | Likely pathogenic | ||
| P3 | chr3:g.169100892G>A | E11 | c.2278C>T p.Pro760Ser | Missense | Deleterious −6.97 | Damaging 0.006 | Probably damaging 1.000 | Disease causing 1.000 | N | Likely pathogenic | ||
| P4 | Chr3:g.169100962_ 169100963delTC | E11 | c.2208-1_2208delGA p.Arg736Ser fs*13 | Deletion frameshift | NA | NA | NA | Disease causing 1.000 | N | Pathogenic | ||
| P5/P6 | chr3:g.169100922G>A (rs864309724) | E11 | c.2248C>T p.Arg750Trp | Missense | Deleterious −6.98 | Damaging 0.000 | Probably damaging 1.000 | Disease causing 1.000 | N | Pathogenic | ||
| P7 | chr3:g.169093016G>A | E13 | c.2542C>T p.Arg848Ter | Nonsense | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P8 | chr3:g.169128041G>T | E4 | c.69C>A p.Cys23Ter | Nonsense | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P9 | chr3:g.169095075C>G | I12 | c.2455+1G>C Loss of splice site | Splice site mutation | NA | NA | NA | Disease causing 1.000 | N | Pathogenic | ||
| P10 | chr3:g.169116194G>A | E7 | c.1114C>T p.Gln372Ter | Nonsense | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P11 | Chr3:g.169095111_ 169095112insT | E12 | c.2419_2420insAp.Arg807Lys fs*7 | Insertion frameshift | NA | NA | NA | Disease causing 1.000 | N | Likely pathogenic | ||
| P12 | chr3:g.169095235A>G | E12 | c.2296T>C p.Cys766Arg | Missense | Deleterious −10.12 | Damaging 0.000 | Possibly damaging 0.845 | Disease causing 1.000 | N | Likely pathogenic | ||
| P13 | chr3:g.169116402G>C | E7 | c.906C>G p.Ser302Arg | Missense | Neutral −1.53 | Tolerated 0.071 | Probably damaging 0.999 | Disease causing 1.000 | N | Uncertain significance | ||
| P14/P15 | chr3:g.169095082T>C (rs200049869) | E12 | c.2449A>G p.Met817Val | Missense | Neutral 0.16 | Tolerated 0.706 | Benign 0.000 | Disease causing 0.949 | ExAc: Y (0.0004/45) 1000G: N | Uncertain significance | ||
| P16/P17/ P18 | chr3:g.169143748C>A (rs116535717) | E2 | c.-105G>T?c | 5′UTR | NA | NA | NA | Disease causing 0.529 | ExAc: Y (0.0047/561) 1000G: Y (0.0068/34) | Benign | ||
| P19 | chr3:g.169122674T>C (rs34896995) | E5 | c.320A>G p.Gln107Arg | Missense | Neutral −2.26 | Damaging 0.030 | Possibly damaging 0.946 | Disease causing 1.000 | ExAc: (0.0026/319) 1000G: (0.0010/5) | Uncertain significance | ||
| P20 | chr3:g.169145034T>C (rs370795924) | 5′UTR | 5′UTR | NA | NA | NA | Disease causing 1.000 | N (1 individual48 ) | Uncertain significance | |||
| P16/P17/ P18TF1-1 | chr3:g.169143748C>A (rs116535717) | E3* | c.88G>T p.Ala30Ser* | Missense* | Neutral −1.11 | Damaging 0.003 | Possibly damaging 0.548 | Disease causing 0.529 ExAc: 561/120542 1000G: 34 | Benign | |||
The table lists all mutations found in this study, together with the results from different algorithms analyzing the potential effects on protein structure and function (bold font indicates novel mutations). The last column lists the results of the classification of the mutations using the recommendations of the American College of Medical Genetics and the Association for Molecular Pathology (supplemental Table 2).12 Only patients P1 to P12 with mutations judged to be pathogenic or likely pathogenic were included in further phenotypic analysis.
ACMG, American College of Medical Genetics and Genomics; CDS, coding sequence; MAC, minor allele count; MAF, minor allele frequency; N, no; NA, not applicable; UTR, untranslated region; Y, yes.
All designations in the table except for the last row refer to MECOM transcript variant 3 (NM_001105078.3, NP_001098548.2). Designations for transcript variant 1 (NM_001105077.3, NP_001098547.3) are added for mutation rs116535717, located in the 5′-UTR of transcript variant 3 (Figure 1).