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Center for Computational Systems Medicine
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Fusion Gene and Fusion Protein Summary

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Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)

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Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)

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Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)

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Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)

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Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)

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Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)

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Potential target of CAR-T therapy development

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Information on the samples that have these potential fusion neoantigens

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Fusion Protein Targeting Drugs - (Manual Curation)

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Fusion Protein Related diseases - (Manual Curation)

Fusion Protein:RAPGEF5-STK4

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: RAPGEF5-STK4
FusionPDB ID: 72253
FusionGDB2.0 ID: 72253
HgeneTgene
Gene symbol

RAPGEF5

STK4

Gene ID

9771

6789

Gene nameRap guanine nucleotide exchange factor 5serine/threonine kinase 4
SynonymsGFR|MR-GEF|REPACKRS2|MST1|YSK3
Cytomap

7p15.3

20q13.12

Type of geneprotein-codingprotein-coding
Descriptionrap guanine nucleotide exchange factor 5M-Ras-regulated GEFM-Ras-regulated Rap GEFRap guanine nucleotide exchange factor (GEF) 5guanine nucleotide exchange factor for Rap1related to Epacserine/threonine-protein kinase 4STE20-like kinase MST1kinase responsive to stress 2mammalian STE20-like protein kinase 1mammalian sterile 20-like 1serine/threonine-protein kinase Krs-2
Modification date2020031320200313
UniProtAcc.

Q13043

Main function of 5'-partner protein: FUNCTION: Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes. {ECO:0000250|UniProtKB:Q9JI11, ECO:0000269|PubMed:11278283, ECO:0000269|PubMed:11517310, ECO:0000269|PubMed:12757711, ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:16510573, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18986304, ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:21212262, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:21512132, ECO:0000269|PubMed:8702870, ECO:0000269|PubMed:8816758}.
Ensembl transtripts involved in fusion geneENST idsENST00000344041, ENST00000405243, 
ENST00000401957, ENST00000475788, 
ENST00000487587, ENST00000372801, 
ENST00000372806, ENST00000396731, 
ENST00000499879, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score16 X 14 X 10=224013 X 13 X 7=1183
# samples 2116
** MAII scorelog2(21/2240*10)=-3.41503749927884
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(16/1183*10)=-2.88630626345243
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: RAPGEF5 [Title/Abstract] AND STK4 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: RAPGEF5 [Title/Abstract] AND STK4 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)RAPGEF5(22347958)-STK4(43607084), # samples:1
Anticipated loss of major functional domain due to fusion event.RAPGEF5-STK4 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF.
RAPGEF5-STK4 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF.
RAPGEF5-STK4 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF.
RAPGEF5-STK4 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF.
* DoF score (Degree of Frequency) = # partners X # break points X # cancer types
** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10)

check button Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez
PartnerGeneGO IDGO termPubMed ID
TgeneSTK4

GO:0000902

cell morphogenesis

11805089

TgeneSTK4

GO:0001934

positive regulation of protein phosphorylation

19962960

TgeneSTK4

GO:0006468

protein phosphorylation

8566796|11805089

TgeneSTK4

GO:0006915

apoptotic process

21212262

TgeneSTK4

GO:0018105

peptidyl-serine phosphorylation

16751106

TgeneSTK4

GO:0032092

positive regulation of protein binding

22292086

TgeneSTK4

GO:0033138

positive regulation of peptidyl-serine phosphorylation

19962960

TgeneSTK4

GO:0035329

hippo signaling

20412773

TgeneSTK4

GO:0035556

intracellular signal transduction

8566796

TgeneSTK4

GO:0043065

positive regulation of apoptotic process

15109305

TgeneSTK4

GO:0046777

protein autophosphorylation

11805089

TgeneSTK4

GO:0050821

protein stabilization

19962960



check button Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr7:22347958/chr20:43607084)
- FGviewer provides the online visualization of the retention search of the protein functional features across DNA, RNA, protein, and pathological levels.
- How to search
1. Put your fusion gene symbol.
2. Press the tab key until there will be shown the breakpoint information filled.
4. Go down and press 'Search' tab twice.
4. Go down to have the hyperlink of the search result.
5. Click the hyperlink.
6. See the FGviewer result for your fusion gene.
FGviewer

check buttonRetention analysis results of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features, are available here.

check buttonFusion gene breakpoints across RAPGEF5 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure

check buttonFusion gene breakpoints across STK4 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure


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Fusion Amino Acid Sequences


check buttonFusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandSeq length
(transcript)
BP loci
(transcript)
Predicted start
(transcript)
Predicted stop
(transcript)
Seq length
(amino acids)
ENST00000344041RAPGEF5chr722347958-ENST00000372806STK4chr2043607084+666553411881626
ENST00000344041RAPGEF5chr722347958-ENST00000396731STK4chr2043607084+180753411806602
ENST00000344041RAPGEF5chr722347958-ENST00000372801STK4chr2043607084+240953411806601
ENST00000344041RAPGEF5chr722347958-ENST00000499879STK4chr2043607084+559253411716571
ENST00000405243RAPGEF5chr722347958-ENST00000372806STK4chr2043607084+689576492111700
ENST00000405243RAPGEF5chr722347958-ENST00000396731STK4chr2043607084+203776492036675
ENST00000405243RAPGEF5chr722347958-ENST00000372801STK4chr2043607084+263976492036675
ENST00000405243RAPGEF5chr722347958-ENST00000499879STK4chr2043607084+582276491946645

check buttonDeepORF prediction of the coding potential based on the fusion transcript sequence of in-frame fusion genes. DeepORF is a coding potential classifier based on convolutional neural network by comparing the real Ribo-seq data. If the no-coding score < 0.5 and coding score > 0.5, then the in-frame fusion transcript is predicted as being likely translated.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandNo-coding scoreCoding score
ENST00000344041ENST00000372806RAPGEF5chr722347958-STK4chr2043607084+0.0007148620.99928516
ENST00000344041ENST00000396731RAPGEF5chr722347958-STK4chr2043607084+0.0028658720.9971341
ENST00000344041ENST00000372801RAPGEF5chr722347958-STK4chr2043607084+0.0016262250.99837375
ENST00000344041ENST00000499879RAPGEF5chr722347958-STK4chr2043607084+0.0010917680.9989083
ENST00000405243ENST00000372806RAPGEF5chr722347958-STK4chr2043607084+0.001394820.9986052
ENST00000405243ENST00000396731RAPGEF5chr722347958-STK4chr2043607084+0.007866770.9921332
ENST00000405243ENST00000372801RAPGEF5chr722347958-STK4chr2043607084+0.0049966390.9950034
ENST00000405243ENST00000499879RAPGEF5chr722347958-STK4chr2043607084+0.002276560.9977234

check button Predicted full-length fusion amino acid sequences. For individual full-length fusion transcript sequence from FusionPDB, we ran ORFfinder and chose the longest ORF among all the predicted ones.

Get the fusion protein sequences from here.

Fusion protein sequence information is available in the fasta format.
>FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP

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Fusion Protein Breakpoint Sequences for RAPGEF5-STK4

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
RAPGEF5chr722347958STK4chr2043607084534178VPLIPARGGICELSYGSVYKAIHKET
RAPGEF5chr722347958STK4chr2043607084764252VPLIPARGGICELSYGSVYKAIHKET

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Potential FusionNeoAntigen Information of RAPGEF5-STK4 in HLA I

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.
RAPGEF5-STK4_22347958_43607084.msa

check button Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)
Fusion geneHchrHbpTgeneTchrTbpHLA IFusionNeoAntigen peptideBinding scoreImmunogenic scoreNeoantigen start (at BP 13)Neoantigen end (at BP 13)
RAPGEF5-STK4chr722347958chr2043607084534HLA-B44:03CELSYGSVY0.99670.90751019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:01CELSYGSVY0.99570.9331019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B15:03CELSYGSVY0.05160.55191019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B27:05ARGGICELSY0.99970.833515
RAPGEF5-STK4chr722347958chr2043607084534HLA-B27:04ARGGICELSY0.99960.7519515
RAPGEF5-STK4chr722347958chr2043607084534HLA-B27:02ARGGICELSY0.99960.5605515
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:01ICELSYGSVY0.47150.7471919
RAPGEF5-STK4chr722347958chr2043607084534HLA-B27:03ARGGICELSY0.9970.846515
RAPGEF5-STK4chr722347958chr2043607084534HLA-B44:26CELSYGSVY0.99670.90751019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B44:07CELSYGSVY0.99670.90751019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B44:13CELSYGSVY0.99670.90751019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:04CELSYGSVY0.99670.93751019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:07CELSYGSVY0.99620.91051019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:08CELSYGSVY0.99580.85341019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:05CELSYGSVY0.99570.9331019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:06CELSYGSVY0.99380.93641019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:03CELSYGSVY0.97180.92931019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:11CELSYGSVY0.8360.8821019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B35:28CELSYGSVY0.69540.76241019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B35:20CELSYGSVY0.64330.78581019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B15:53CELSYGSVY0.32260.66791019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B48:02CELSYGSVY0.14290.74021019
RAPGEF5-STK4chr722347958chr2043607084534HLA-B27:08ARGGICELSY0.99960.7308515
RAPGEF5-STK4chr722347958chr2043607084534HLA-B27:10ARGGICELSY0.99960.8623515
RAPGEF5-STK4chr722347958chr2043607084534HLA-B15:53ICELSYGSVY0.77710.6258919
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:11ICELSYGSVY0.6280.6346919
RAPGEF5-STK4chr722347958chr2043607084534HLA-B18:05ICELSYGSVY0.47150.7471919

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Potential FusionNeoAntigen Information of RAPGEF5-STK4 in HLA II

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.

check button Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).
Fusion geneHchrHbpTgeneTchrTbpHLA IIFusionNeoAntigen peptideNeoantigen start (at BP 13)Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of RAPGEF5-STK4

check button3D structures of the fusion breakpoint peptide of 14AA sequence that have potential fusion neoantigens
* The minimum length of the amino acid sequence in RoseTTAFold is 14AA. Here, we predicted the 14AA fusion protein breakpoint sequence not the fusion neoantigen peptide, which is shorter than 14 AA.
File nameBPseqHgeneTgeneHchrHbpTchrTbpAAlen
7864RGGICELSYGSVYKRAPGEF5STK4chr722347958chr2043607084534

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of RAPGEF5-STK4

check buttonVirtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.
HLA allelePDB IDFile nameBPseqDocking scoreGlide score
HLA-B14:023BVN7864RGGICELSYGSVYK-7.15543-7.26883
HLA-B14:023BVN7864RGGICELSYGSVYK-4.77435-5.80965
HLA-B52:013W397864RGGICELSYGSVYK-6.80875-6.92215
HLA-B52:013W397864RGGICELSYGSVYK-4.20386-5.23916
HLA-A11:014UQ27864RGGICELSYGSVYK-7.5194-8.5547
HLA-A11:014UQ27864RGGICELSYGSVYK-6.9601-7.0735
HLA-A24:025HGA7864RGGICELSYGSVYK-7.52403-7.63743
HLA-A24:025HGA7864RGGICELSYGSVYK-5.82433-6.85963
HLA-B27:056PYJ7864RGGICELSYGSVYK-3.28285-4.31815
HLA-B44:053DX87864RGGICELSYGSVYK-5.91172-6.94702
HLA-B44:053DX87864RGGICELSYGSVYK-4.24346-4.35686

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Vaccine Design for the FusionNeoAntigens of RAPGEF5-STK4

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptide sequenceFusionNeoAntigen RNA sequence
RAPGEF5-STK4chr722347958chr20436070841019CELSYGSVYCTGTGAACTGTCCTATGGCAGCGTATA
RAPGEF5-STK4chr722347958chr2043607084515ARGGICELSYTGCCAGAGGTGGCATCTGTGAACTGTCCTA
RAPGEF5-STK4chr722347958chr2043607084919ICELSYGSVYCATCTGTGAACTGTCCTATGGCAGCGTATA

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptideFusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of RAPGEF5-STK4

check button These samples were reported as having these fusion breakpoints. For individual breakpoints, we checked the open reading frames considering multiple gene isoforms and chose the in-frame fusion genes only. Then, we made fusion protein sequences and predicted the fusion neoantigens. These fusion-positive samples may have these potential fusion neoantigens.
Cancer typeFusion geneHchrHbpHenstTchrTbpTenstSample
STADRAPGEF5-STK4chr722347958ENST00000344041chr2043607084ENST00000372801TCGA-BR-8077-01A

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Potential target of CAR-T therapy development for RAPGEF5-STK4

check button Predicted 3D structure. We used RoseTTAFold.

check buttonRetention analysis result of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, to provide the retention of the transmembrane domain, we only show the protein feature retention information of those transmembrane features


* Minus value of BPloci means that the break point is located before the CDS.
- In-frame and retained 'Transmembrane'.
PartnerGeneHbpTbpENSTStrandBPexonTotalExonProtein feature loci*BPlociTotalLenProtein featureProtein feature note

check button Subcellular localization prediction of the transmembrane domain retained fusion proteins
* We used DeepLoc 1.0. The order of the X-axis of the barplot is as follows: Entry_ID, Localization, Type, Nucleus, Cytoplasm, Extracellular, Mitochondrion, Cell_membrane, Endoplasmic_reticulum, Plastid, Golgi.apparatus, Lysosome.Vacuole, Peroxisome. Y-axis is the output score of DeepLoc. Clicking the image will open a new tab with a large image.
HgeneHchrHbpHenstTgeneTchrTbpTenstDeepLoc result

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Related Drugs to RAPGEF5-STK4

check button Drugs used for this fusion-positive patient.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDrugSourcePMID

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Related Diseases to RAPGEF5-STK4

check button Diseases that have this fusion gene.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDiseaseSourcePMID

check button Diseases associated with fusion partners.
(DisGeNet 4.0)
PartnerGeneDisease IDDisease name# pubmedsSource