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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:ARHGAP35-ESR1

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: ARHGAP35-ESR1
FusionPDB ID: 6088
FusionGDB2.0 ID: 6088
HgeneTgene
Gene symbol

ARHGAP35

ESR1

Gene ID

2909

2099

Gene nameRho GTPase activating protein 35estrogen receptor 1
SynonymsGRF-1|GRLF1|P190-A|P190A|p190ARhoGAP|p190RhoGAPER|ESR|ESRA|ESTRR|Era|NR3A1
Cytomap

19q13.32

6q25.1-q25.2

Type of geneprotein-codingprotein-coding
Descriptionrho GTPase-activating protein 35glucocorticoid receptor DNA-binding factor 1glucocorticoid receptor repression factor 1rho GAP p190Aestrogen receptorE2 receptor alphaER-alphaestradiol receptorestrogen nuclear receptor alphaestrogen receptor alpha E1-E2-1-2estrogen receptor alpha E1-N2-E2-1-2nuclear receptor subfamily 3 group A member 1oestrogen receptor alpha
Modification date2020031320200329
UniProtAcc

Q9NRY4

Main function of 5'-partner protein: FUNCTION: Rho GTPase-activating protein (GAP) (PubMed:19673492, PubMed:28894085). Binds several acidic phospholipids which inhibits the Rho GAP activity to promote the Rac GAP activity (PubMed:19673492). This binding is inhibited by phosphorylation by PRKCA (PubMed:19673492). Involved in cell differentiation as well as cell adhesion and migration, plays an important role in retinal tissue morphogenesis, neural tube fusion, midline fusion of the cerebral hemispheres and mammary gland branching morphogenesis (By similarity). Transduces signals from p21-ras to the nucleus, acting via the ras GTPase-activating protein (GAP) (By similarity). Transduces SRC-dependent signals from cell-surface adhesion molecules, such as laminin, to promote neurite outgrowth. Regulates axon outgrowth, guidance and fasciculation (By similarity). Modulates Rho GTPase-dependent F-actin polymerization, organization and assembly, is involved in polarized cell migration and in the positive regulation of ciliogenesis and cilia elongation (By similarity). During mammary gland development, is required in both the epithelial and stromal compartments for ductal outgrowth (By similarity). Represses transcription of the glucocorticoid receptor by binding to the cis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'; this function is however unclear and would need additional experimental evidences (PubMed:1894621). {ECO:0000250|UniProtKB:P81128, ECO:0000250|UniProtKB:Q91YM2, ECO:0000269|PubMed:1894621, ECO:0000269|PubMed:19673492, ECO:0000269|PubMed:28894085}.

P03372

Main function of 5'-partner protein: FUNCTION: Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1. {ECO:0000269|PubMed:10681512, ECO:0000269|PubMed:10816575, ECO:0000269|PubMed:11477071, ECO:0000269|PubMed:11682626, ECO:0000269|PubMed:14764652, ECO:0000269|PubMed:15078875, ECO:0000269|PubMed:15891768, ECO:0000269|PubMed:16043358, ECO:0000269|PubMed:16617102, ECO:0000269|PubMed:16684779, ECO:0000269|PubMed:17922032, ECO:0000269|PubMed:17932106, ECO:0000269|PubMed:18247370, ECO:0000269|PubMed:19350539, ECO:0000269|PubMed:20074560, ECO:0000269|PubMed:20705611, ECO:0000269|PubMed:21330404, ECO:0000269|PubMed:22083956, ECO:0000269|PubMed:7651415, ECO:0000269|PubMed:9328340}.
Ensembl transtripts involved in fusion geneENST idsENST00000404338, ENST00000598548, 
ENST00000406599, ENST00000427531, 
ENST00000482101, ENST00000206249, 
ENST00000338799, ENST00000440973, 
ENST00000443427, ENST00000456483, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score19 X 11 X 9=188110 X 10 X 6=600
# samples 1912
** MAII scorelog2(19/1881*10)=-3.30742852519225
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(12/600*10)=-2.32192809488736
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: ARHGAP35 [Title/Abstract] AND ESR1 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: ARHGAP35 [Title/Abstract] AND ESR1 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)ARHGAP35(47440665)-ESR1(152201789), # samples:1
Anticipated loss of major functional domain due to fusion event.ARHGAP35-ESR1 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.
ARHGAP35-ESR1 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.
ARHGAP35-ESR1 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.
ARHGAP35-ESR1 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
TgeneESR1

GO:0006366

transcription by RNA polymerase II

15831516

TgeneESR1

GO:0010629

negative regulation of gene expression

21695196

TgeneESR1

GO:0030520

intracellular estrogen receptor signaling pathway

9841876

TgeneESR1

GO:0032355

response to estradiol

15304487

TgeneESR1

GO:0043124

negative regulation of I-kappaB kinase/NF-kappaB signaling

7651415|16043358

TgeneESR1

GO:0043433

negative regulation of DNA-binding transcription factor activity

10816575

TgeneESR1

GO:0043627

response to estrogen

11581164

TgeneESR1

GO:0045893

positive regulation of transcription, DNA-templated

9841876|20074560

TgeneESR1

GO:0045899

positive regulation of RNA polymerase II transcriptional preinitiation complex assembly

9841876

TgeneESR1

GO:0045944

positive regulation of transcription by RNA polymerase II

11544182|12047722|15345745|15831516|18563714

TgeneESR1

GO:0051091

positive regulation of DNA-binding transcription factor activity

9328340|10681512

TgeneESR1

GO:0071392

cellular response to estradiol stimulus

15831516



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/chr19:47440665/chr6:152201789)
- 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 ARHGAP35 (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 ESR1 (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)
ENST00000404338ARHGAP35chr1947440665+ENST00000440973ESR1chr6152201789+92793826049701656
ENST00000404338ARHGAP35chr1947440665+ENST00000338799ESR1chr6152201789+50583826049701656
ENST00000404338ARHGAP35chr1947440665+ENST00000456483ESR1chr6152201789+89433826046341544
ENST00000404338ARHGAP35chr1947440665+ENST00000443427ESR1chr6152201789+92793826049701656
ENST00000404338ARHGAP35chr1947440665+ENST00000206249ESR1chr6152201789+92763826049701656

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
ENST00000404338ENST00000440973ARHGAP35chr1947440665+ESR1chr6152201789+0.0002419560.99975806
ENST00000404338ENST00000338799ARHGAP35chr1947440665+ESR1chr6152201789+0.0008355080.99916446
ENST00000404338ENST00000456483ARHGAP35chr1947440665+ESR1chr6152201789+0.0001387920.99986124
ENST00000404338ENST00000443427ARHGAP35chr1947440665+ESR1chr6152201789+0.0002419560.99975806
ENST00000404338ENST00000206249ARHGAP35chr1947440665+ESR1chr6152201789+0.0002429330.9997571

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 ARHGAP35-ESR1

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
ARHGAP35chr1947440665ESR1chr615220178938261275IFIERCIEYIEATGHNDYMCPATNQC

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Potential FusionNeoAntigen Information of ARHGAP35-ESR1 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.
ARHGAP35-ESR1_47440665_152201789.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)
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:01IEATGHNDY0.98530.7445918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B44:03IEATGHNDY0.96590.7674918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B35:04EATGHNDYM0.25630.86461019
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B35:02EATGHNDYM0.25630.86461019
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B35:12EATGHNDYM0.25630.86461019
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:04IEATGHNDY0.99080.7651918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:05IEATGHNDY0.98530.7445918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:06IEATGHNDY0.97720.7375918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B44:13IEATGHNDY0.96590.7674918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B44:26IEATGHNDY0.96590.7674918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B44:07IEATGHNDY0.96590.7674918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:03IEATGHNDY0.96480.7294918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:11IEATGHNDY0.78250.6423918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B35:09EATGHNDYM0.25630.86461019
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B15:53IEATGHNDY0.17870.7282918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B48:02IEATGHNDY0.04350.7934918
ARHGAP35-ESR1chr1947440665chr61522017893826HLA-B18:11YIEATGHNDY0.7560.6345818

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Potential FusionNeoAntigen Information of ARHGAP35-ESR1 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 ARHGAP35-ESR1

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
3663IEYIEATGHNDYMCARHGAP35ESR1chr1947440665chr61522017893826

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of ARHGAP35-ESR1

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-B53:011A1O3663IEYIEATGHNDYMC-2.59389-2.70729
HLA-B51:011E283663IEYIEATGHNDYMC-1.89526-2.00866
HLA-B51:011E283663IEYIEATGHNDYMC-0.577834-1.61313
HLA-B57:032BVO3663IEYIEATGHNDYMC-3.28732-3.40072
HLA-A03:012XPG3663IEYIEATGHNDYMC-3.36386-3.47726
HLA-A03:012XPG3663IEYIEATGHNDYMC-2.06038-3.09568
HLA-B14:023BVN3663IEYIEATGHNDYMC-3.69242-4.72772
HLA-B14:023BVN3663IEYIEATGHNDYMC-3.63266-3.74606
HLA-B44:033DX73663IEYIEATGHNDYMC-0.815673-0.929073
HLA-B52:013W393663IEYIEATGHNDYMC-3.33521-4.37051
HLA-B52:013W393663IEYIEATGHNDYMC-2.97357-3.08697
HLA-B18:014JQV3663IEYIEATGHNDYMC-3.13531-3.24871
HLA-B18:014JQV3663IEYIEATGHNDYMC-2.04878-3.08408
HLA-A11:014UQ23663IEYIEATGHNDYMC-6.44719-6.56059
HLA-A11:014UQ23663IEYIEATGHNDYMC-5.19647-6.23177
HLA-A24:025HGA3663IEYIEATGHNDYMC-5.41298-6.44828
HLA-A24:025HGA3663IEYIEATGHNDYMC-5.00657-5.11997
HLA-B57:015VUD3663IEYIEATGHNDYMC-3.3536-3.467
HLA-B27:056PYJ3663IEYIEATGHNDYMC-3.9605-4.0739
HLA-B27:056PYJ3663IEYIEATGHNDYMC-2.49607-3.53137
HLA-B27:036PZ53663IEYIEATGHNDYMC-2.26983-2.38323
HLA-B27:036PZ53663IEYIEATGHNDYMC-1.24741-2.28271
HLA-B44:053DX83663IEYIEATGHNDYMC-4.97345-5.08685
HLA-B44:053DX83663IEYIEATGHNDYMC-2.09523-3.13053
HLA-B44:021M6O3663IEYIEATGHNDYMC-5.98168-6.09508
HLA-B44:021M6O3663IEYIEATGHNDYMC0.169477-0.865823
HLA-B07:025EO03663IEYIEATGHNDYMC-3.24778-3.36118
HLA-A02:016TDR3663IEYIEATGHNDYMC-5.35165-6.38695
HLA-A02:016TDR3663IEYIEATGHNDYMC-4.33415-4.44755

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Vaccine Design for the FusionNeoAntigens of ARHGAP35-ESR1

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
ARHGAP35-ESR1chr1947440665chr61522017891019EATGHNDYMAAGCCACAGGACATAACGACTATATGT
ARHGAP35-ESR1chr1947440665chr6152201789818YIEATGHNDYACATTGAAGCCACAGGACATAACGACTATA
ARHGAP35-ESR1chr1947440665chr6152201789918IEATGHNDYTTGAAGCCACAGGACATAACGACTATA

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 ARHGAP35-ESR1

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
BRCAARHGAP35-ESR1chr1947440665ENST00000404338chr6152201789ENST00000206249TCGA-A8-A06O

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Potential target of CAR-T therapy development for ARHGAP35-ESR1

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 ARHGAP35-ESR1

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 ARHGAP35-ESR1

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