Table 2. Validated Splicing Mutations in COSMIC Cancer Gene Census genes in TCGA tumor genomes.
| Gene | Splice Mutation | R i (bits) | Tumor | Observed Splicing Event |
|---|---|---|---|---|
| CASC5 |
15:40942786G>A
(c.6212+5G>A) |
4.8 > 1.7
(Natural Site) |
AML | The natural donor site of
CASC5 exon 19 (NM_144508.4) is weakened,
leading to a significant increase in intron inclusion. |
| DNMT3A |
2:25467022A>G
(c.1851+2T>C) |
3.6 > -3.5
(Natural Site) |
AML | The natural donor site of
DNMT3A exon 15 (NM_022552.4) is abolished,
resulting in a significant increase in total exon skipping and intron inclusion. |
| STAG2 |
X:123176495G>A
(c.462G>A) |
6.5 > 3.5
(Natural Site) |
BLCA | The natural donor of
STAG2 exon 6 (NM_006603.4) is weakened, and a
significant amount of exon 6 skipping is observed. |
| STAG2 |
X:123200024G>A
(c.2097-1G>A) |
19.5 > 8.6
(Natural Site) |
BLCA | The natural acceptor of
STAG2 exon 21 (NM_006603.4) is weakened,
resulting in a significant increase in exon 21 skipping. |
| ATM |
11:108214098G>T
(c.8418G>T) |
8.7 > 5.1
(Natural Site) |
BRCA | A natural donor site is weakened, leading to a significant increase in
ATM exon 57 (NM_000051.3) skipping events. Some reads with mutation are involved in wildtype splicing (leaky splicing). |
| BARD1 |
2:215645882A>T
(c.716T>A) |
0.9 > 3.1
(Cryptic Site) |
BRCA | The mutation strengthens a cryptic site within
BARD1 exon 4
(NM_000465.2). Reads which use activated cryptic site contain the mutation (one exception). Some reads with mutation are involved in wildtype splicing (leaky splicing). |
| GATA3 |
10:8115701G>C
(c.1048-1G>C) |
0.9 > -10.7
(Natural Site) |
BRCA | The mutation abolishes the natural acceptor of
GATA3 exon 6
(NM_002051.2). This both increases the use of a pre-existing exonic cryptic splice site (4.2 > 5.6 bits; leads to an 8nt deletion) and significantly increases total intron inclusion. |
| TP53 |
17:7577609C>T
(c.673-1G>A) |
6.0 > -4.9
(Natural Site) |
BRCA | A natural acceptor site is abolished, activating a cryptic site 49nt
upstream (R i=5.2 bits) of TP53 exon 7 (NM_000546.5). |
| POLD1 |
19:50920353A>G
(c.3119A>G) |
8.6 > 6.1
(Natural Site) |
COAD | The natural donor of
POLD1 exon 25 (NM_002691.3) is weakened,
leading to a significant increase in total exon skipping. |
| SMAD3 |
15:67482748C>G
(c.1155-3C>G) |
11.9>3.1|-4.0 > 7.7
( Natural | Cryptic) |
COAD | This mutation both weakens the natural acceptor of
SMAD3 exon 9
(NM_005902.3) and creates a cryptic site (does not appear to be used). A significant amount intron inclusion reads are observed. Use of a distant pre-existing cryptic acceptor (9.6 bits; 3598nt from natural acceptor) was. |
| PIK3R1 |
5:67591246A>G
(c.936-2A>G) |
7.5 > -7.3
(Natural Site) |
GBM | The natural acceptor of
PIK3R1 exon 8 (NM_181504.3) is abolished,
which promotes a significant increase in exon 8 skipping. |
| FAT1 |
4:187521515C>A
(c.11641-1G>T) |
5.3 > -2.4
(Natural Site) |
HNSC | The natural acceptor of
FAT1 exon 22 (NM_005245.3) is abolished,
resulting in both intron inclusion (total intron inclusion and the use of a 2.3 bit cryptic site 82nt upstream of natural acceptor) and use of two exonic cryptic sites (237nt and 234nt from natural acceptor; Ri=1.0 bits and -0.2 bits, respectively). |
| TGFBR2 |
3:30729875G>A
(c.1397-1G>A) |
8.4 > -2.5
(Natural Site) |
HNSC |
TGFBR2 exon 6 natural acceptor (NM_003242.5) is abolished, leading
to multiple splicing events: intron inclusion, use of three cryptic sites (35nt exonic [R i=3.7 bits], 30nt and 972nt intronic [R i=0.4 bits and 11.2 bits, respectively]), and exon 6 and 7 skipping (uses a novel exon ~55kb downstream of exon 7). |
| PBRM1 |
3:52682355C>G
(c.813+5G>C) |
6.8 > 2.9
(Natural Site) |
KIRC | The natural donor of
PBRM1 exon 8 (NM_018313.4) is weakened, which
leads to a significant increase in exon 8 skipping. |
| PBRM1 |
3:52685756A>G
(c.714+2T>C) |
7.7 > 0.7
(Natural Site) |
KIRC | The natural donor of
PBRM1 exon 7 (NM_018313.4) is abolished,
resulting in a significant increase in total exon skipping. |
| SETD2 |
3:47079269T>A
(c.7239-2A>T) |
9.8 > 2.1| 6.4 > 9.0
( Natural | Cryptic) |
KIRC | This mutation both significantly weakens the natural acceptor of
SETD2
exon 18 (NM_014159.6) while strengthening a 4nt exonic cryptic site, which is used. |
| RB1 |
13:49027249T>A
(c.1814+2T>A) |
4.9 >-13.7
(Natural Site) |
LUAD | The natural donor of
RB1 exon 18 (NM_000321.2) is abolished, leading
to a significant increase in both exon skipping and intron inclusion. All intron inclusion reads contain the mutation of interest. |
| RBM10 |
X:47006900G>T
(c.17+3G>T) |
7.8 > 4.1
(Natural Site) |
LUAD | The natural donor of
RBM10 exon 2 (NM_005676.4) is weakened,
leading to a significant increase in exon 2 skipping. |
| RBM10 |
X:47028898G>T
(c.201+1G>T) |
8.7 > -9.9
(Natural Site) |
LUAD |
RBM10 exon 3 (NM_005676.4) natural donor is abolished. RNAseq
reads which overlap the exon-intron junction are observed (all reads contain mutation). Use of cryptic donor (61nt upstream of donor; R i=1.7 bits) is observed as well. |
| DDX5 |
17:62500098 TACAG>T
(c.441+2delACAG) |
-1.3 > 5.4
(Cryptic Site) |
PRAD | The mutation creates a 5.4 bit cryptic donor within
DDX5 exon 4
(NM_004396.3), which would lead to a 4nt deletion of exon 4. Note that wildtype splicing is still the dominant isoform observed. |
| PTEN |
10:89690802G>A
(c.210-1G>A) |
8.5 > -2.3
(Natural Site) |
PRAD | The natural acceptor of
PTEN exon 5 (NM_000314.4) is abolished,
leading to an increased amount of total exon 5 skipping. |
| NRAS |
1:115258669A>G
(c.111+2T>C) |
8.1 > 1.1
(Natural Site) |
SKCM | The mutation abolishes the natural donor of
NRAS exon 2
(NM_002524.4), which promotes a significant increase in exon 2 skipping |
| PPP6C |
9:127933364C>T
(c.171G>A) |
6.7 > 3.7
(Natural Site) |
SKCM | The mutation weakens
PPP6C exon 2 (NM_002721.4) natural donor,
leading to increased intron inclusion. All reads which cross the junction contain the mutation. A intronic cryptic site is also activated (110nt downstr.; R i=6.4 bits). |
| PPP6C |
9:127923119C>G
(c.237+1G>C) |
6.8 > -11.8
(Natural Site) |
SKCM | This mutation abolishes the natural donor of
PPP6C exon 3
(NM_002721.4), resulting in a significant increase in exon 3 skipping. |
| BAP1 |
3:52442512T>C
(c.233A>G) |
1.9 > 5.1
(Cryptic Site) |
UVM | A cryptic donor within
BAP1 exon 4 (NM_004656.3) is strengthened,
leading to a significant increase in its use. Its use leads to a 27 nt deletion of exon 4. |
Example mutations which alter splicing in tumor-associated genes found in patients with the same tumor type. Mutations are linked to their page on https://validsplicemut.cytognomix.com/, which provides additional material such as RNAseq images of the regions of interest. GRCh37 coordinates provided.