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. 2019 Mar 1;27(7):1143–1156. doi: 10.1038/s41431-019-0369-6

Table 4.

Relevant locus information for 16 and 33 loci used to predict the tramadol to O-desmethyltramadol ratio (T:M1) and the t-MP at the most stringent feature inclusion threshold (i.e., all listed single-nucleotide variants were used in >75% of supervised machine learning cross-validation folds)

Gene hg19/GRCh37 Genome reference cDNA position rs Number Alternate DNA changes (Ref > Alt) ΔAmino acida CADD (Phred) SIFT (Score) PolyPhen-v2 (Score) Used to predict
UGT2B7 NC_000004.11:g.69962282G>A NM_001074.2:g.90G>A NM_001074.2:c.44G>A 0.135 Tolerated (0.110) Benign (0.0310) T:M1
UGT2B7 NC_000004.11:g.69962349G>T NM_001074.2:c.111G>T rs1255338508 p.(Met37Ile) 0.004 Tolerated (1.00) Benign (0.0750) T:M1
UGT2B7 NC_000004.11:g.69962583C>T NM_001074.2:g.391C>T NM_001074.2:c.345C>T rs1453130551 7.24 T:M1
UGT2B7 NC_000004.11:g.69962586G>C NM_001074.2:c.348G>C rs772560918 p.(Met116Ile) 0.121 Tolerated (0.385) Benign (0.00300) T:M1
UGT2B7 NC_000004.11:g.69962610A>G NM_001074.2:c.372A>G rs28365063 p.(Arg124Ser) 0.009 t-MP
UGT2B7 NC_000004.11:g.69964232A>C NM_001074.2:g.747A>C NM_001074.2:c.722-726A>C 2.37 T:M1
UGT2B7 NC_000004.11:g.69978319G>A NM_001074.2:c.1455G>C p.(Trp485*) 36 T:M1
UGT2B7 NC_000004.11:g.69978334T>C NM_001074.2:g.1516T>C NM_001074.2:c.1470T>C 0.005 T:M1
OPRM1 NC_000006.11:g.154360666C>T NM_001145279.2:c.266C>T rs199648369 p.(Pro89Leu) 21.4 Deleterious (0) Benign (0) t-MP
OPRM1 NC_000006.11:g.154407714dup NC_000006.11(OPRM1_v008):c.570-3247dup NM_001145279.2:c.570-3247dup rs101840062 1.25 t-MP
OPRM1 NC_000006.11:g.154408673C>T NC_000006.11(OPRM1_v008):c.570-2288C>T NM_001145279.2:c.570-2288C>T 5.66 T:M1
OPRM1 NC_000006.11:g.154412242delC NM_001145279.2:c.1078delC p.(Leu360Serfs*60) 34 T:M1
OPRM1 NC_000006.11:g.154412881A>C NC_000006.11(OPRM1_v008):c.1443 + 274A>C NM_001145279.2:c.1443 + 274A>C 4.67 T:M1
OPRM1 NC_000006.11:g.154414312T>C NC_000006.11(OPRM1_v008):c.1443 + 1705T>C NM_001145279.2:c.1443 + 1705T>C 4.57 t-MP
OPRM1 NC_000006.11:g.154414459G>A NM_001145279.2:c.1443 + 1852G>A p.(Val407Met) 3.27 Deleterious (0.0400) Benign (0.00300) t-MP
OPRM1 NC_000006.11:g.154414611G>A NG_021208.2:g.87976G>A NM_001145279.2:c.1443 + 2004 G>A rs200646591 5.17 T:M1
OPRM1 NC_000006.11:g.154414678G>A NC_000006.11(OPRM1_v008):c.1443 + 2071G>A NM_001145279.2:c.1443 + 2071G>A 14.8 T:M1
OPRM1 NC_000006.11:g.154428905C>A NM_001145279.2:c.1444–10913C>A rs1357614491 C>T p.(Ala396Asp) 2.99 Deleterious (0) Benign (0.00900) t-MP
OPRM1 NC_000006.11:g.154429092dup NC_000006.11(OPRM1_v008):c.1444-10726dup NM_001145279.2:c.1444-10726dup rs1319935018 0.796 T:M1
OPRM1 NC_000006.11:g.154430035A>T NC_000006.11(OPRM1_v008):c.1444-9783A>T NM_001145279.2:c.1444-9783A>T 0.162 T:M1
OPRM1 NC_000006.11:g.154439693G>A NC_000006.11(OPRM1_v008):c.1444-125G>A NM_001145279.2:c.1444-125G>A 1.01 t-MP
OPRM1 NC_000006.11:g.154439699C>T NC_000006.11(OPRM1_v008):c.1444-119C>T NM_001145279.2:c.1444-119C>T 2.38 T:M1
OPRM1 NC_000006.11:g.154439986_154439987delCT NC_000006.11(OPRM1_v042):c.*130_*131del NM_001145279.2:c.*130_131delCT 9 T:M1
OPRM1 NC_000006.11:g.154440143delT NG_021208.2:g.241572delT NM_001145279.2:c.*287delT 9.15 T:M1
OPRM1 NC_000006.11:g.154440379T>A NG_021208.2:g.113744T>A NM_001145279.2:c.*523T>A rs1252162127 9.57 T:M1
OPRM1 NC_000006.11:g.154567680C>G NG_021208.2:g.241046C>G NM_001005803.1:c.246 + 45C>G 6.36 T:M1
ABCB1 NC_000007.13:g.87138569G>A NG_011513.1:g.208996C>T NM_000927.4:c.3489 + 22C>T G>C, G>T 1.84 t-MP
ABCB1 NC_000007.13:g.87144642C>A NM_000927.4:c.3187G>T rs761914266 p.(Gly1063Cys) 35 Deleterious (0) Probably damaging (0.996) t-MP
ABCB1 NC_000007.13:g.87144644T>C NM_000927.4:c.3185A>G p.(Lys1062Arg) 17.5 Tolerated (0.185) Benign (0.0250) T:M1
ABCB1 NC_000007.13:g.87165761A>C NG_011513.1:g.181804T>G NM_000927.4:c.2481 + 13T>G 2.39 t-MP
ABCB1 NC_000007.13:g.87175444C>T NG_011513.1:g.172121G>A NM_000927.4:c.1726-104G>A 9.3 T:M1
ABCB1 NC_000007.13:g.87178819C>T NM_000927.4:c.1570G>A p.(Val524Ile) 28.3 Deleterious (0) Probably damaging (0.818) T:M1
ABCB1 NC_000007.13:g.87179086G>A NG_011513.1:g.168479C>T NM_000927.4:c.1554 + 81C>T rs2235035 0.167 t-MP
ABCB1 NC_000007.13:g.87179342G>T NM_000927.4:c.1379C>A p.(Thr460Asn) 18.8 Tolerated (0.0900) Benign (0.0165) T:M1
ABCB1 NC_000007.13:g.87179361C>T NM_000927.4:c.1360G>A p.(Asp454Asn) 32 Deleterious (0.0100) Probably damaging (0.782) T:M1
ABCB1 NC_000007.13:g.87179532T>C NM_000927.4:c.1305A>G p.(Thr435=) 0.033 T:M1
ABCB1 NC_000007.13:g.87183666dup NG_011513.1:g.163912dup NM_000927.4:c.828-405dup rs5885589 insAA, insAAA, insAAAAA 3.26 t-MP
ABCB1 NC_000007.13:g.87214505A>C NG_011513.1:g.133060T>G NM_000927.4:c.286 + 323T>G A>C, A>T 1.04 t-MP
ABCB1 NC_000007.13:g.87214740G>T NG_011513.1:g.132825C>A NM_000927.4:c.286 + 88C>A 4.11 T:M1
ABCB1 NC_000007.13:g.87214994A>G NM_000927.4:c.120T>C p.(Phe40=) 15.7 T:M1
ABCB1 NC_000007.13:g.87229912C>T NG_011513.1:g.117653G>A NM_000927.4:c.-7 + 159G>A 11.4 T:M1
ABCB1 NC_000007.13:g.87230159C>A NG_011513.1:g.117406G>T NM_000927.4:c.-95G>T 13.1 T:M1
COMT NC_000022.10:g.19929314C>T NG_011526.1:g.25800C>T NM_006440.3:c.13C>T 12.2 Deleterious (0.0600) Benign (0.0618) T:M1
COMT NC_000022.10:g.19951173G>A NM_000754.3:c.374G>A rs759305975 p.(Arg125His) 25.2 Deleterious (0.0100) Probably damaging (1.00) t-MP
COMT NC_000022.10:g.19951174C>T NM_000754.3:c.375C>T rs1223964672 p.(Arg125=) 23.6 T:M1
COMT NC_000022.10:g.19957537G>A NG_011526.1:g.33275G>A NM_000754.3:c.*1278G>A 10.1 T:M1
CYP2D6 NC_000022.10:g.42522312T>C NG_008376.3:g.8682G>A NM_000106.5:c.*75 + 189G>A rs116390392 2.19 T:M1 and t-MP
CYP2D6 NC_000022.10:g.42528224G>A NG_008376.3:g.2775C>T NM_000106.5:c.-1426C>T rs28588594 1.33 t-MP

t-MP toxicologically inferred metabolizer phenotype, CADD Combined Annotation Dependent Depletion

aExon positions are as follows: UGT2B7 NM_001074.2:c.-46_721 (exon 1), NM_001074.2:c.722_870 (exon 2), NM_001074.2:c.871_1002 (exon 3), NM_001074.2:c.1003_1090 (exon 4), NM_001074.2:c.1091_1310 (exon 5), 1311_*251 (exon 6); OPRM1 NM_001145279.2:c.-523_-1 (exon 1), NM_001145279.2:c.1_145 (exon 2), NM_001145279.2:c.146_569 (exon 3), NM_001145279.2:c.570_922 (exon 4), NM_001145279.2:c.923_1443 (exon 5), NM_001145279.2:c.1444_*738; ABCB1 NM_000927.4:c.-493_-331 (exon 1), NM_000927.4:c.-330_-7 (exon 2), NM_000927.4:c.-6_68 (exon 3), NM_000927.4:c.69-117 (exon 4), NM_000927.4:c.118_286 (exon 5), NM_000927.4:c.287_338 (exon 6), NM_000927.4:c.339_530 (exon 7), NM_000927.4:c.531_702 (exon 8), NM_000927.4:c.703_827 (exon 9), NM_000927.4:c.828_999 (exon 10), NM_000927.4:c.1000_1113 (exon 11), NM_000927.4:c.1114_1224 (exon 12), NM_000927.4:c.1225_1350 (exon 13), NM_000927.4:c.1351_1554 (exon 14), NM_000927.4:c.1555_1725 (exon 15), NM_000927.4:c.1726_1887 (exon 16), NM_000927.4:c.1888_2064 (exon 17), NM_000927.4:c.2065_2211 (exon 18), NM_000927.4:c.2212_2319 (exon 19), NM_000927.4:c.2320_2397 (exon 20), NM_000927.4:c.2398_2482 (exon 21), NM_000927.4:c.2482_2685 (exon 22), NM_000927.4:c.2686_2786 (exon 23), NM_000927.4:c.2787_2927 (exon 24), NM_000927.4:c.2928_3084 (exon 25), NM_000927.4:c.3085_3282 (exon 26), NM_000927.4:c.3283_3489 (exon 27), NM_000927.4:c.3490_3636 (exon 28), NM_000927.4:c.3637_*380 (exon 29); COMT NM_000754.3:c.-249_-92 (exon 1), NM_000754.3:c.-91_-1 (exon 2), NM_000754.3:c.1_289 (exon 3), NM_000754.3:c.290_483 (exon 4), NM_000754.3:c.484_615 (exon 5), NM_000754.3:c.616_*1239; CYP2D6 NM_000106.5:c.-90_180 (exon 1), NM_000106.5:c.181_352 (exon 2), NM_000106.5:c. 353_505 (exon 3), NM_000106.5:c.506_666 (exon 4), NM_000106.5:c.667_843 (exon 5), NM_000106.5:c.844_985 (exon 6), NM_000106.5:c.986_1173 (exon 7), NM_000106.5:c.1174_1315 (exon 8), NM_000106.5:c.1316_*75 (exon 9)