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Fusion Protein:ATG5-MLLT4

Fusion Gene and Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: ATG5-MLLT4
	FusionPDB ID: 7595
	FusionGDB2.0 ID: 7595
		Hgene	Tgene
	Gene symbol	ATG5	MLLT4
	Gene ID	9474	4301
	Gene name	autophagy related 5	afadin, adherens junction formation factor
	Synonyms	APG5\|APG5-LIKE\|APG5L\|ASP\|SCAR25\|hAPG5	AF6\|MLL-AF6\|MLLT4\|l-afadin
	Cytomap	6q21	6q27
	Type of gene	protein-coding	protein-coding
	Description	autophagy protein 5APG5 autophagy 5-likeATG5 autophagy related 5 homologapoptosis-specific protein	afadinALL1-fused gene from chromosome 6 proteinmyeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4myeloid/lymphoid or mixed-lineage leukemia; translocated to, 4protein AF-6
	Modification date	20200313	20200322
	UniProtAcc	Q9H1Y0 Main function of 5'-partner protein: FUNCTION: Involved in autophagic vesicle formation. Conjugation with ATG12, through a ubiquitin-like conjugating system involving ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. Involved in mitochondrial quality control after oxidative damage, and in subsequent cellular longevity. Plays a critical role in multiple aspects of lymphocyte development and is essential for both B and T lymphocyte survival and proliferation. Required for optimal processing and presentation of antigens for MHC II. Involved in the maintenance of axon morphology and membrane structures, as well as in normal adipocyte differentiation. Promotes primary ciliogenesis through removal of OFD1 from centriolar satellites and degradation of IFT20 via the autophagic pathway. {ECO:0000250\|UniProtKB:Q99J83, ECO:0000269\|PubMed:12207896, ECO:0000269\|PubMed:20580051, ECO:0000269\|PubMed:22170153, ECO:0000269\|PubMed:26812546}.; FUNCTION: May play an important role in the apoptotic process, possibly within the modified cytoskeleton. Its expression is a relatively late event in the apoptotic process, occurring downstream of caspase activity. Plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD. {ECO:0000269\|PubMed:15778222, ECO:0000269\|PubMed:7796880}.; FUNCTION: (Microbial infection) May act as a proviral factor. In association with ATG12, negatively regulates the innate antiviral immune response by impairing the type I IFN production pathway upon vesicular stomatitis virus (VSV) infection (PubMed:17709747). Required for the translation of incoming hepatitis C virus (HCV) RNA and, thereby, for initiation of HCV replication, but not required once infection is established (PubMed:19666601). {ECO:0000269\|PubMed:17709747, ECO:0000269\|PubMed:19666601}.	.
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000360666, ENST00000343245, ENST00000369070, ENST00000369076, ENST00000475645,	ENST00000344191, ENST00000351017, ENST00000366806, ENST00000392108, ENST00000392112, ENST00000400822, ENST00000447894, ENST00000507679,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	25 X 16 X 9=3600	8 X 5 X 6=240
	# samples	29	8
	** MAII score	log2(29/3600*10)=-3.6338721012021 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(8/240*10)=-1.58496250072116 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Fusion gene context	PubMed: ATG5 [Title/Abstract] AND MLLT4 [Title/Abstract] AND fusion [Title/Abstract]
Fusion neoantigen context	PubMed: ATG5 [Title/Abstract] AND MLLT4 [Title/Abstract] AND neoantigen [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	ATG5(106649847)-MLLT4(168265231), # samples:1
Anticipated loss of major functional domain due to fusion event.	ATG5-MLLT4 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. ATG5-MLLT4 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)

Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner

Gene

GO ID

GO term

PubMed ID

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr6:106649847/chr6:168265231)
- 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.

Retention 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.

Fusion gene breakpoints across ATG5 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Fusion gene breakpoints across MLLT4 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

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Fusion Amino Acid Sequences

Fusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	Seq length (transcript)	BP loci (transcript)	Predicted start (transcript)	Predicted stop (transcript)	Seq length (amino acids)
ENST00000369070	ATG5	chr6	106649847	-	ENST00000344191	MLLT4	chr6	168265231	+	5859	887	869	5779	1636
ENST00000369070	ATG5	chr6	106649847	-	ENST00000351017	MLLT4	chr6	168265231	+	6433	887	869	6277	1802
ENST00000369070	ATG5	chr6	106649847	-	ENST00000392108	MLLT4	chr6	168265231	+	7452	887	869	5737	1622
ENST00000369070	ATG5	chr6	106649847	-	ENST00000392112	MLLT4	chr6	168265231	+	8101	887	869	6013	1714
ENST00000369070	ATG5	chr6	106649847	-	ENST00000366806	MLLT4	chr6	168265231	+	8344	887	869	6256	1795
ENST00000369070	ATG5	chr6	106649847	-	ENST00000447894	MLLT4	chr6	168265231	+	6257	887	869	6256	1796
ENST00000369070	ATG5	chr6	106649847	-	ENST00000400822	MLLT4	chr6	168265231	+	8375	887	869	6286	1805
ENST00000369076	ATG5	chr6	106649847	-	ENST00000344191	MLLT4	chr6	168265231	+	5987	1015	997	5907	1636
ENST00000369076	ATG5	chr6	106649847	-	ENST00000351017	MLLT4	chr6	168265231	+	6561	1015	997	6405	1802
ENST00000369076	ATG5	chr6	106649847	-	ENST00000392108	MLLT4	chr6	168265231	+	7580	1015	997	5865	1622
ENST00000369076	ATG5	chr6	106649847	-	ENST00000392112	MLLT4	chr6	168265231	+	8229	1015	997	6141	1714
ENST00000369076	ATG5	chr6	106649847	-	ENST00000366806	MLLT4	chr6	168265231	+	8472	1015	997	6384	1795
ENST00000369076	ATG5	chr6	106649847	-	ENST00000447894	MLLT4	chr6	168265231	+	6385	1015	997	6384	1796
ENST00000369076	ATG5	chr6	106649847	-	ENST00000400822	MLLT4	chr6	168265231	+	8503	1015	997	6414	1805

DeepORF 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.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	No-coding score	Coding score
ENST00000369070	ENST00000344191	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.007362946	0.99263704
ENST00000369070	ENST00000351017	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.004231994	0.9957681
ENST00000369070	ENST00000392108	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.001198455	0.9988016
ENST00000369070	ENST00000392112	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.001157188	0.99884284
ENST00000369070	ENST00000366806	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.000933401	0.99906665
ENST00000369070	ENST00000447894	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.004949919	0.99505013
ENST00000369070	ENST00000400822	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.002475465	0.99752456
ENST00000369076	ENST00000344191	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.008056357	0.9919436
ENST00000369076	ENST00000351017	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.004586811	0.99541324
ENST00000369076	ENST00000392108	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.001339152	0.9986608
ENST00000369076	ENST00000392112	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.001335308	0.99866474
ENST00000369076	ENST00000366806	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.001073688	0.99892634
ENST00000369076	ENST00000447894	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.005325725	0.9946742
ENST00000369076	ENST00000400822	ATG5	chr6	106649847	-	MLLT4	chr6	168265231	+	0.00286573	0.9971342

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 ATG5-MLLT4

+/-13 AA sequence from the breakpoints of the fusion protein sequences.

Hgene

Hchr

Hbp

Tgene

Tchr

Tbp

Length(fusion protein)

BP in fusion protein

Peptide

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Potential FusionNeoAntigen Information of ATG5-MLLT4 in HLA I

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.

Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)

Fusion gene

Hchr

Hbp

Tgene

Tchr

Tbp

HLA I

FusionNeoAntigen peptide

Binding score

Immunogenic score

Neoantigen start (at BP 13)

Neoantigen end (at BP 13)

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Potential FusionNeoAntigen Information of ATG5-MLLT4 in HLA II

Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).

Fusion gene

Hchr

Hbp

Tgene

Tchr

Tbp

HLA II

FusionNeoAntigen peptide

Neoantigen start (at BP 13)

Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of ATG5-MLLT4

3D 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.

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of ATG5-MLLT4

Virtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.

HLA allele

PDB ID

File name

BPseq

Docking score

Glide score

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Vaccine Design for the FusionNeoAntigens of ATG5-MLLT4

mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.

Fusion gene

Hchr

Hbp

Tchr

Tbp

Start in +/-13AA

End in +/-13AA

FusionNeoAntigen peptide sequence

FusionNeoAntigen RNA sequence

mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.

Fusion gene

Hchr

Hbp

Tchr

Tbp

Start in +/-13AA

End in +/-13AA

FusionNeoAntigen peptide

FusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of ATG5-MLLT4

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 type

Fusion gene

Hchr

Hbp

Henst

Tchr

Tbp

Tenst

Sample

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Potential target of CAR-T therapy development for ATG5-MLLT4

Predicted 3D structure. We used RoseTTAFold.

Retention 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'.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

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.

Hgene

Hchr

Hbp

Henst

Tgene

Tchr

Tbp

Tenst

DeepLoc result

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Related Drugs to ATG5-MLLT4

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

Hgene

Tgene

Drug

Source

PMID

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Related Diseases to ATG5-MLLT4

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

Hgene

Tgene

Disease

Source

PMID

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner

Gene

Disease ID

Disease name

# pubmeds

Source

	Fusion Gene and Fusion Protein Summary
	Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)
	Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)
	Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)
	Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)
	Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)
	Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)
	Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)
	Potential target of CAR-T therapy development
	Information on the samples that have these potential fusion neoantigens
	Fusion Protein Targeting Drugs - (Manual Curation)
	Fusion Protein Related diseases - (Manual Curation)