Table 2. Representative Validated Splicing Mutations in COSMIC Cancer Gene Census genes.
| 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 depict wildtype, 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 this activated cryptic site contain the mutation (one exception). Some reads with mutation depict wildtype, 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 overall 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 overall exon skipping. |
| SMAD3 |
15:67482748C>G
(c.1155-3C>G) |
11.9 > 3.1|-4.0 > 7.7
( Natural | Cryptic) |
COAD | This mutation weakens the natural acceptor of
SMAD3 exon 9
(NM_005902.3) and predicts a cryptic site that does not appear to be used. A significant number of intron inclusion reads are observed. A distant pre-existing cryptic acceptor (9.6 bits; 3,598nt from natural acceptor) was used in multiple reads. |
| 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 (overall 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 the natural acceptor; R i=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 (activates a novel pseudo 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 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. 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 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 splice junction contain the mutation. An intronic cryptic site is also activated (110nt downstream; 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 pre-existing cryptic donor within
BAP1 exon 4 (NM_004656.3) is
strengthened, leading to a significant increase in its use. This mutation leads to a 27 nt deletion in the mutated exon 4 mRNA. |
Example mutations which alter splicing in tumor-associated genes found in patients with these tumor types. Mutations are hyperlinked to their ValidSpliceMut Beacon page, which provides additional material such as IGV images of the RNAseq evidence for the regions of interest. GRCh37 coordinates are indicated