An innovative method to add value to the silent mutations in cancer

1. Why do the silent mutations matter?
By Mehis Pold
1
Why do the silent mutations matter?
Why should an NGS pipeline enable splice site analysis?
Silent mutations are usually of low or no priority in pipelines interpreting NGS
genetic findings because their impact is hard to fathom. Unless such pipelines,
however, have a robust, up to date capacity to map variants to exon-intron
boundaries, important clues may be missed.
I wrote a splice-site analysis tool, a perl-script to be specific, which maps genomic
variants to the exon-intron boundaries as provided by CCDS and UCSC table
browser. My goal was to elucidate how many entries in the version 67 of COSMIC
(the Catalogue of Somatic Mutations in Cancer) annotated as ‘Confirmed somatic
variant’ and ‘Substitution - coding silent’ map to the acceptor site ‘+1 position’ (see
the below figure, red arrow) because this position can be considered conserved in
the U2 intron-exon junctions.
I found a total of 124 variant ‘+1’ acceptor positions annotated as ‘Substitution -
coding silent’ and ‘Confirmed somatic variant’ in COSMIC (see the below table).
Curiously, COSMIC provides no annotations relative to splice sites, and hence, the
variants matching the ones in COSMIC should most certainly analyzed in regard to
the splice acceptor and donor coordinates. Otherwise, the potentially pathogenic
variants can very simply be overlooked.
PLUS STRAND
GENE_ID Zygosity GRCh37 genome position
ABCB5 het 7:20778606-20778606
ACTR10 het 14:58669573-58669573
CHD9 het 16:53301839-53301839
DIEXF het 1:210016796-210016796
DOCK5 het 8:25193755-25193755
HECW1 het 7:43581468-43581468
IRX6 het 16:55361498-55361498
INTRON EXON
-2 -1 +1
Splice acceptor site
EXON
Splice donor site

2. Why do the silent mutations matter?
By Mehis Pold
2
LGR6 het 1:202273687-202273687
LGR6 het 1:202275996-202275996
NPSR1 het 7:34889177-34889177
OPN4 het 10:88419652-88419652
PTEN het 10:89685270-89685270
RNF17 het 13:25374504-25374504
RUNDC3B het 7:87369107-87369107
UPK3B het 7:76143264-76143264
ACPP 3:132056300-132056300
ATP6V0A2 12:124229429-124229429
BCORL1 23:129189829-129189829
BMPR1B 4:96035871-96035871
CA14 1:150236993-150236993
CCDC132_ENST00000305866 7:92978023-92978023
CCDC60 12:119926564-119926564
CKMT2 5:80548514-80548514
CNGA3 2:98999851-98999851
CNKSR2 23:21549974-21549974
CNOT8 5:154250221-154250221
COL5A1 9:137593017-137593017
CROT 7:87022264-87022264
CSF2RB 22:37322029-37322029
EXOSC2 9:133570879-133570879
EYA2 20:45633581-45633581
FANK1 10:127685989-127685989
FAR2 12:29446233-29446233
FBLN2 3:13679062-13679062
FRY 13:32745149-32745149
GABRA5 15:27159950-27159950
GINS1 20:25398741-25398741
GMNN 6:24781705-24781705
HGSNAT_ENST00000458501 8:43024316-43024316
HSF2 6:122741280-122741280
HSPA12B 20:3725549-3725549
ITGB1BP3 19:3941069-3941069
KAZN 1:15428039-15428039
LDB3 10:88477721-88477721
MCF2L 13:113735527-113735527
MFF 2:228220393-228220393
OXSR1_ENST00000311806 3:38291457-38291457
PDE1B 12:54962968-54962968
PLEKHH2 2:43939364-43939364

3. Why do the silent mutations matter?
By Mehis Pold
3
PNLDC1 6:160237001-160237001
PODN 1:53546400-53546400
RALYL 8:85762215-85762215
RASGRP3 2:33747022-33747022
RGS6 14:72961860-72961860
RNF217 6:125404010-125404010
RPS6KB2 11:67200208-67200208
RYR2 1:237868513-237868513
SDCBP 8:59494245-59494245
SGSM2 17:2267890-2267890
SLC12A1 15:48551397-48551397
SPAG16 2:214794684-214794684
TATDN3 1:212970454-212970454
TM4SF4 3:149216509-149216509
TRPM8 2:234845997-234845997
TYRO3 15:41853737-41853737
WWP2 16:69951612-69951612
ZYG11B 1:53282204-53282204
MINUS STRAND
GENE_ID Zygosity GRCh37 genome position
ACD het 16:67691587-67691587
AP3B2 het 15:83330674-83330674
COBL het 7:51261286-51261286
FAM70A het 23:119425195-119425195
HERC1 het 15:63961897-63961897
MAP4K2 het 11:64557096-64557096
PDCD10 het 3:167405481-167405481
PRKG2 het 4:82013606-82013606
PTPRT het 20:40828028-40828028
RGS11 het 16:319382-319382
SIK3 het 11:116744772-116744772
SLC2A1 het 1:43394704-43394704
STAT1 het 2:191843727-191843727
XRCC1 het 19:44051129-44051129
ERCC6 hom 10:50679166-50679166
MMP1 hom 11:102667893-102667893
PRKG2 hom 4:82013606-82013606
ABCA2 9:139906470-139906470
ACLY 17:40061911-40061911
ACOX2 3:58510332-58510332

4. Why do the silent mutations matter?
By Mehis Pold
4
ARHGAP17 16:24971073-24971073
AWAT2 23:69262236-69262236
BTBD2 19:1987252-1987252
C9orf140 9:139960120-139960120
CDH24 14:23524562-23524562
CYP3A7 7:99313529-99313529
DENND1A 9:126392755-126392755
DPP4 2:162881449-162881449
ELL 19:18557290-18557290
FSHR 2:49191105-49191105
GLMN 1:92735333-92735333
HEATR1 1:236718764-236718764
IDH2 15:90628140-90628140
IGDCC3 15:65621935-65621935
LEPRE1 1:43213469-43213469
LGI3 8:22011552-22011552
LRRIQ3 1:74575237-74575237
MAP4K3 2:39570593-39570593
NDUFB7 19:14677077-14677077
NEK10_ENST00000341435 3:27257371-27257371
PHF8 23:54011660-54011660
PIH1D1 19:49950356-49950356
PRMT5 14:23397824-23397824
PSD 10:104164484-104164484
PXDNL_ENST00000356297 8:52252313-52252313
REN 1:204131291-204131291
RP11-1280I22.1 5:138723610-138723610
SAFB2 19:5591804-5591804
SCAP 3:47465535-47465535
SGK1 6:134495218-134495218
SLC20A2 8:42286360-42286360
SPC24 19:11258793-11258793
STAG1 3:136170989-136170989
TBC1D2B 15:78322512-78322512
TMC6 17:76116913-76116913
UXT 23:47516689-47516689
ZFR 5:32390543-32390543