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Table 2 RNA splicing- dedicated in silico analyses for the VUS identified in our study

From: Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds

Patient ID Genomic position (GRCh37) Gene Exon Nucleotide change (cNomen) Predicted protein change (pNomen) dbSNPrsID Non-Finnish European population frequency* Reference splice site-dedicated analyses Cryptic splice site-dedicated analyses ESR-dedicated analyses
Nearest reference MES scores SSFL scores Potential local splice effect Local MES scores ∆tESRseq ∆Hzei ΔΨ
Distance Type WT Var VAR vs WT WT Var VAR vs WT WT Var
(nt) (3′ or 5’ss) ∆ (%) ∆ (%)
688 chr_16_68835593_G_A CDH1 3 c.184G > A p.Gly62Ser 587,781,898 5.99e-05 21 3’ 8.17477 8.17477 0 86.5179 86.5179 0     − 1.44947 10.35 −1.24
chr2_47703664_G_A MSH2 13 c.2164G > A p.Val722Ile 587,781,996 8.99e-05 −47 5’ 10.8583 10.8583 0 100 100 0     0.59756 10.51 −0.01
chr_8_90983475_C_A NBN 6 c.628G > T p.Val210Phe 61,754,796 0.0008158 44 3’ 6.19815 6.19815 0 86.8244 86.8244 0     − 0.782222 −46.21 − 0.15
1873 chr_5_56155672_A_G MAP3K1 3 c.764A > G p.Asn255Ser 56,069,227 0.0269 −71 5’ 7.52484 7.52484 0 78.4708 78.4708 0 New Acceptor Site? 8.8 −1.18661 6.7 −0.04
5378 chr 12_133244944_G_A POLE 19 c.2171C > T p.Ala724Val 61,734,163 0.00030 −3 5’ 9.89081 8.73118 −11.7 86.6769 82.5488 −4.8 New Donor Site? 6.3 −2.14822 −32.05 −0.16
6031 chr17_41245621_T_C BRCA1 10 c.1927A > G p.Ser643Gly 80,357,105 NA 1257 3’ 8.86265 8.86265 0 87.3058 87.3058 0     1.44078 58.08 0.02
  AXIN2 10 c.2272G > A p.Ala758Thr 145,007,501 0.0039861 35 3’ 6.34671 6.34671 0 86.1925 86.1925 0     −0.942617 0.12 −0.09
chr5_112102960_C_T APC 4 c.295C > T p.Arg99Trp 139,196,838 0.0006444 75 3’ 7.49577 7.49577 0 84.8039 84.8039 0     −2.2189 −14.34 − 0.08
12,470   AXIN2 10 c.2272G > A p.Ala758Thr 145,007,501 0.0039861 35 3’ 6.34671 6.34671 0 86.1925 86.1925 0     −0.942617 0.12 − 0.09
chr5_112128218_G_A APC 7 c.721G > A p.Glu241Lys 777,603,154 0.0001818 −9 5’ 7.15277 7.15277   87.0697 87.0697 0     −1.51981 −49.76 −0.42
12,852 chr_14_69061228_G_A RAD51B RAD51B 11 c.1063G > A p.Ala355Thr 61,758,785 0.0071658 27 3’ 11.8 11.8 0 80.2 80.2 0 −1.24035 −50.64
88,295 chr10_89690828_G_A PTEN PTEN 4 c.235G > A p.Ala79Thr 202,004,587 0.0001678 −19 5’ 9.6515 9.6515 0 86.8647 86.8647 0     −1.39321 10.77 0.6
900,178 chr11_94197365_C_T MRE11A MRE11A 11 c.1139G > A p.Arg380His 587,781,646 4.5e-05 41 3’ 8.9941 8.9941 0 95.7456 95.7456 0     −1.57887 −48.78 −0.03
960,579 chr_5_56177843_C_G MAP3K1 14 c.2816C > G p.Ser939Cys 45,556,841 0.0221 447 3’ 12.0063 12.0063 0 100 100 0 −0.486881 −16.1 0
1,000,459 chr13_28537449_ACTT_A CDX2 3 c.742_744del p.Lys248delAAG 553,066,746 0.0001682 55 3’ 11.7045 11.7045 0 87.4307 87.4307 0     −2.46964 −100.08
1,100,948 chr_17_7133187_A_G DVL2 DVL2 5 c.596 T > C p.Met199Thr 372,715,697 6.01e-05 −61 5’ 6.34467 6.34467 0 80.4452 80.4452 0     0.0509416 −1.77 0.54
chr2_47641430_C_T MSH2 5 c.815C > T p.Ala272Val 34,136,999 0.0003755 23 3’ 10.3527 10.3527 0 84.3224 84.3224 0     −2.17832 −46.5 −0.03
10,002,068 chr_17_63526198_C_T AXIN2 11 c.2428G > A p.Asp810Asn 140,344,858 1.5e-05 23 3’ 11.6727 11.6727 0 87.3948 87.3948 0     −1.22987 −14.33
10,005,829 chr_14_69061228_G_A RAD51B 11 c.1063G > A p.Ala355Thr 61,758,785 0.0071658 27 3’ 11.8 11.8 0 80.2 80.2 0 −1.24035 −50.64
chr8_90993640_C_T NBN 3 c.283G > A p.Asp95Asn 61,753,720 0.0030459 −38 5’ 10.7663 10.7663 0 94.6711 94.6711 0     0.318238 24.6 0.03
chr_11_108155132_G_A ATM 26 c.3925G > A p.Ala1309Thr 149,711,770 0.0009147    9.98517 9.98517 0 84.8076 84.8076 0     0.676556 32.96 0.04
12,001,161 chr_14_68353893_A_G RAD51B 7 c.728A > G p.Lys243Arg 34,594,234 0.010682 −29 5’ 9.09184 9.09184 0 78.9497 78.9497 0 Cryptic 5’ss activation? 0.9 7.9 −1.48785 −40.54 −0.19
12,015,576 chr19_15291551_C_G NOTCH3 19 c.3083G > C p.Trp1028Ser rs146829488 na −60 5’ 11.1124 11.1124 0 82.5954 82.5954 0     0.300115 −6.4 0.1
11,717 chr1_45797881_C_T MUTYH 10 c.881G > A p.Cys294Tyr rs879254257 na −44 5’ 6.31089 6.31089 0 72.818 72.818 0     1.09496 −7.06 0.04
17,161 chr_11_108139187_T_A ATM 18 c.2689 T > A p.Phe897Ile 147,122,522 4.5e-05 51 3’ 9.8979 9.8979 0 93.4253 93.4253 0     0.554269 87.95 0.01
22 chr_12_133241897_A_G POLE 21 c.2459 T > C p.Met820Thr 767,460,640 0 −10 5’ 6.58677 6.58677 0 77.9039 77.9039 0     1.28743 −2.13 0.06
chr_14_68352672_A_G RAD51B 6 c.539A > G p.Tyr180Cys 28,910,275 0.0045906 −34 5’ 9.54919 9.54919 0 83.7411 83.7411 0     0.881539 7.23 −0.19
chr_5_56155672_A_G MAP3K1 3 c.764A > G p.Asn255Ser 56,069,227 0.0269 −71 5’ 7.52484 7.52484 0 78.4708 78.4708 0 New Acceptor Site? 8.8 −1.18661 6.7 −0.04
6207 chr_17_63530163_C_T AXIN2 10 c.2272G > A p.Ala758Thr 145,007,501 0.0039861 35 3’ 6.34671 6.34671 0 86.1925 86.1925 0     −0.942617 0.12 −0.09
6475 chr_17_33433488_G_A RAD51D 6 c.493C > T p.Arg165Trp 544,654,228 6.94e-05 13 3’ 8.20686 8.20686 0 85.1161 85.1161 0     −2.55724 −22.32 1.42
  1. na not available; *Non-Finnish European population based on ExAC database; NM for APC: NM_000038; ATM: NM_000051; AXIN2: NM_004655; BRCA1: NM_007300; CDH1: NM_004360; CDX2: NM_001265; DVL2: NM_004422; MAP3K1: NM_005921; MSH2: NM_000251; MRE11A: NM_005591; MUTYH: NM_012222; NBN: NM_002485; NOTCH3: NM_000435; POLE: NM_006231; PTEN: NM_000314; RAD51B: NM_133509; RAD51D: NM_002878. In order to predict their biological impact, RNA splicing-dedicated bioinformatics analyses were performed as described under Materials and Methods. Results shown in bold were considered as predictive of a potential variant-induced negative biological effect. MES MaxEntScan, SSFL Splice Site Finder-Like, nt Nucleotide, 3′ or 5’ss 3′ splice site or 5′ splice site, ESR Exonic splicing regulators