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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:NIPBL-ARNTL2

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: NIPBL-ARNTL2
FusionPDB ID: 59189
FusionGDB2.0 ID: 59189
HgeneTgene
Gene symbol

NIPBL

ARNTL2

Gene ID

25836

56938

Gene nameNIPBL cohesin loading factoraryl hydrocarbon receptor nuclear translocator like 2
SynonymsCDLS|CDLS1|IDN3|IDN3-B|Scc2BMAL2|CLIF|MOP9|PASD9|bHLHe6
Cytomap

5p13.2

12p11.23

Type of geneprotein-codingprotein-coding
Descriptionnipped-B-like proteinNipped-B homologSCC2 homologdelanginsister chromatid cohesion 2 homologaryl hydrocarbon receptor nuclear translocator-like protein 2CYCLE-like factorPAS domain-containing protein 9basic-helix-loop-helix-PAS protein MOP9brain and muscle ARNT-like 2class E basic helix-loop-helix protein 6member of PAS protein 9transcrip
Modification date2020031320200313
UniProtAcc

Q6KC79

Main function of 5'-partner protein: FUNCTION: Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with MAU2/SCC4 which mediates the loading of the cohesin complex onto chromatin (PubMed:22628566, PubMed:28914604). Plays a role in cohesin loading at sites of DNA damage. Its recruitment to double-strand breaks (DSBs) sites occurs in a CBX3-, RNF8- and RNF168-dependent manner whereas its recruitment to UV irradiation-induced DNA damage sites occurs in a ATM-, ATR-, RNF8- and RNF168-dependent manner (PubMed:28167679). Along with ZNF609, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others (By similarity). {ECO:0000250|UniProtKB:Q6KCD5, ECO:0000269|PubMed:22628566, ECO:0000269|PubMed:28167679, ECO:0000269|PubMed:28914604}.

Q8WYA1

Main function of 5'-partner protein: FUNCTION: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. {ECO:0000269|PubMed:11018023, ECO:0000269|PubMed:12738229, ECO:0000269|PubMed:14672706}.
Ensembl transtripts involved in fusion geneENST idsENST00000504430, ENST00000282516, 
ENST00000448238, 
ENST00000261178, 
ENST00000266503, ENST00000311001, 
ENST00000395901, ENST00000544915, 
ENST00000546179, ENST00000539558, 
ENST00000542388, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score26 X 13 X 16=54086 X 5 X 5=150
# samples 437
** MAII scorelog2(43/5408*10)=-3.65268658669272
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(7/150*10)=-1.09953567355091
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: NIPBL [Title/Abstract] AND ARNTL2 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: NIPBL [Title/Abstract] AND ARNTL2 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)NIPBL(36972143)-ARNTL2(27521195), # samples:2
Anticipated loss of major functional domain due to fusion event.NIPBL-ARNTL2 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.
NIPBL-ARNTL2 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.
NIPBL-ARNTL2 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.
NIPBL-ARNTL2 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
HgeneNIPBL

GO:0000122

negative regulation of transcription by RNA polymerase II

18854353

HgeneNIPBL

GO:0031065

positive regulation of histone deacetylation

18854353

HgeneNIPBL

GO:0045892

negative regulation of transcription, DNA-templated

18854353

HgeneNIPBL

GO:0071921

cohesin loading

22628566

TgeneARNTL2

GO:0006357

regulation of transcription by RNA polymerase II

12055078

TgeneARNTL2

GO:0007623

circadian rhythm

10864977

TgeneARNTL2

GO:0045893

positive regulation of transcription, DNA-templated

12738229

TgeneARNTL2

GO:0045944

positive regulation of transcription by RNA polymerase II

15147242



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/chr5:36972143/chr12:27521195)
- 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 NIPBL (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 ARNTL2 (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)
ENST00000282516NIPBLchr536972143+ENST00000544915ARNTL2chr1227521195+592113674993144881
ENST00000282516NIPBLchr536972143+ENST00000395901ARNTL2chr1227521195+310413674993102868
ENST00000282516NIPBLchr536972143+ENST00000546179ARNTL2chr1227521195+301113674992925808
ENST00000282516NIPBLchr536972143+ENST00000311001ARNTL2chr1227521195+320613674993204902
ENST00000282516NIPBLchr536972143+ENST00000261178ARNTL2chr1227521195+316113674993102867
ENST00000282516NIPBLchr536972143+ENST00000266503ARNTL2chr1227521195+360913674993246915
ENST00000448238NIPBLchr536972143+ENST00000544915ARNTL2chr1227521195+589013364683113881
ENST00000448238NIPBLchr536972143+ENST00000395901ARNTL2chr1227521195+307313364683071867
ENST00000448238NIPBLchr536972143+ENST00000546179ARNTL2chr1227521195+298013364682894808
ENST00000448238NIPBLchr536972143+ENST00000311001ARNTL2chr1227521195+317513364683173901
ENST00000448238NIPBLchr536972143+ENST00000261178ARNTL2chr1227521195+313013364683071867
ENST00000448238NIPBLchr536972143+ENST00000266503ARNTL2chr1227521195+357813364683215915

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
ENST00000282516ENST00000544915NIPBLchr536972143+ARNTL2chr1227521195+0.0001151650.99988484
ENST00000282516ENST00000395901NIPBLchr536972143+ARNTL2chr1227521195+0.0004501050.9995499
ENST00000282516ENST00000546179NIPBLchr536972143+ARNTL2chr1227521195+0.0006385990.99936146
ENST00000282516ENST00000311001NIPBLchr536972143+ARNTL2chr1227521195+0.0004280690.999572
ENST00000282516ENST00000261178NIPBLchr536972143+ARNTL2chr1227521195+0.0004043670.9995957
ENST00000282516ENST00000266503NIPBLchr536972143+ARNTL2chr1227521195+0.0002544190.99974555
ENST00000448238ENST00000544915NIPBLchr536972143+ARNTL2chr1227521195+0.0001170090.99988294
ENST00000448238ENST00000395901NIPBLchr536972143+ARNTL2chr1227521195+0.0004797280.9995203
ENST00000448238ENST00000546179NIPBLchr536972143+ARNTL2chr1227521195+0.0006779310.99932206
ENST00000448238ENST00000311001NIPBLchr536972143+ARNTL2chr1227521195+0.0004578090.99954224
ENST00000448238ENST00000261178NIPBLchr536972143+ARNTL2chr1227521195+0.000427020.99957293
ENST00000448238ENST00000266503NIPBLchr536972143+ARNTL2chr1227521195+0.0002675090.99973243

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 NIPBL-ARNTL2

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
NIPBLchr536972143ARNTL2chr12275211951336287PQPVCSPAGSEGTPKGKVLREENQCI
NIPBLchr536972143ARNTL2chr12275211951367287PQPVCSPAGSEGTPKGKVLREENQCI

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Potential FusionNeoAntigen Information of NIPBL-ARNTL2 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.
NIPBL-ARNTL2_36972143_27521195.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)
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B45:01SEGTPKGKV0.99060.8668918
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B08:01EGTPKGKVL0.86450.67821019
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A31:06GTPKGKVLR0.7220.65371120
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B41:01SEGTPKGKV0.35730.8159918
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A68:24EGTPKGKVLR0.94810.68211020
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A68:03EGTPKGKVLR0.94270.66221020
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A33:01EGTPKGKVLR0.91080.60111020
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A33:05EGTPKGKVLR0.91080.60111020
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B44:03SEGTPKGKVL0.8350.9228919
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A68:05EGTPKGKVLR0.79820.66611020
NIPBL-ARNTL2chr536972143chr12275211951367HLA-C01:17GTPKGKVL0.98910.98191119
NIPBL-ARNTL2chr536972143chr12275211951367HLA-C01:30GTPKGKVL0.90920.98381119
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A31:01GTPKGKVLR0.89280.71751120
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B14:03EGTPKGKVL0.70070.93351019
NIPBL-ARNTL2chr536972143chr12275211951367HLA-A68:01EGTPKGKVLR0.94810.68211020
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B44:10SEGTPKGKVL0.83350.6156919
NIPBL-ARNTL2chr536972143chr12275211951367HLA-C01:02GTPKGKVL0.98520.98191119
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B08:18EGTPKGKVL0.86450.67821019
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B08:12EGTPKGKVL0.69730.79771019
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B40:04SEGTPKGKVL0.9840.7538919
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B44:13SEGTPKGKVL0.8350.9228919
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B44:07SEGTPKGKVL0.8350.9228919
NIPBL-ARNTL2chr536972143chr12275211951367HLA-B44:26SEGTPKGKVL0.8350.9228919

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Potential FusionNeoAntigen Information of NIPBL-ARNTL2 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 NIPBL-ARNTL2

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
6485PAGSEGTPKGKVLRNIPBLARNTL2chr536972143chr12275211951367

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of NIPBL-ARNTL2

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-B14:023BVN6485PAGSEGTPKGKVLR-7.9962-8.1096
HLA-B14:023BVN6485PAGSEGTPKGKVLR-5.70842-6.74372
HLA-B52:013W396485PAGSEGTPKGKVLR-6.83737-6.95077
HLA-B52:013W396485PAGSEGTPKGKVLR-4.4836-5.5189
HLA-A11:014UQ26485PAGSEGTPKGKVLR-10.0067-10.1201
HLA-A11:014UQ26485PAGSEGTPKGKVLR-9.03915-10.0745
HLA-A24:025HGA6485PAGSEGTPKGKVLR-6.56204-6.67544
HLA-A24:025HGA6485PAGSEGTPKGKVLR-5.42271-6.45801
HLA-B44:053DX86485PAGSEGTPKGKVLR-7.85648-8.89178
HLA-B44:053DX86485PAGSEGTPKGKVLR-5.3978-5.5112
HLA-A02:016TDR6485PAGSEGTPKGKVLR-3.37154-4.40684

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Vaccine Design for the FusionNeoAntigens of NIPBL-ARNTL2

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
NIPBL-ARNTL2chr536972143chr12275211951019EGTPKGKVLCTCCTAAAGGTAAAGTGTTGAGAGAGG
NIPBL-ARNTL2chr536972143chr12275211951020EGTPKGKVLRCTCCTAAAGGTAAAGTGTTGAGAGAGGAGA
NIPBL-ARNTL2chr536972143chr12275211951119GTPKGKVLCTAAAGGTAAAGTGTTGAGAGAGG
NIPBL-ARNTL2chr536972143chr12275211951120GTPKGKVLRCTAAAGGTAAAGTGTTGAGAGAGGAGA
NIPBL-ARNTL2chr536972143chr1227521195918SEGTPKGKVGAACTCCTAAAGGTAAAGTGTTGAGAG
NIPBL-ARNTL2chr536972143chr1227521195919SEGTPKGKVLGAACTCCTAAAGGTAAAGTGTTGAGAGAGG

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 NIPBL-ARNTL2

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
READNIPBL-ARNTL2chr536972143ENST00000282516chr1227521195ENST00000261178TCGA-AG-3731-01A

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Potential target of CAR-T therapy development for NIPBL-ARNTL2

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 NIPBL-ARNTL2

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 NIPBL-ARNTL2

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