Why do the silent mutations matter?
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Silent mutations that occur at the +1 position of splice acceptor sites can impact splicing even though they do not change the encoded amino acid. The author analyzed the Catalogue of Somatic Mutations in Cancer and found 124 variants annotated as silent mutations that actually occur at conserved splice acceptor sites, which may have pathogenic effects by altering splicing. Next-generation sequencing analysis pipelines should include splice site mapping to avoid missing potentially important clues from variants affecting splicing.
Why do the silent mutations matter?
- 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