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Fusion Protein:CLYBL-PCCA

Fusion Gene and Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: CLYBL-PCCA
	FusionPDB ID: 17479
	FusionGDB2.0 ID: 17479
		Hgene	Tgene
	Gene symbol	CLYBL	PCCA
	Gene ID	171425	5095
	Gene name	citramalyl-CoA lyase	propionyl-CoA carboxylase subunit alpha
	Synonyms	CLB	-
	Cytomap	13q32.3	13q32.3
	Type of gene	protein-coding	protein-coding
	Description	citramalyl-CoA lyase, mitochondrial(3S)-malyl-CoA thioesterasebeta-methylmalate synthasecitrate lyase beta likecitrate lyase subunit beta-like protein, mitochondrialmalate synthase	propionyl-CoA carboxylase alpha chain, mitochondrialPCCase alpha subunitpccA complementation grouppropanoyl-CoA:carbon dioxide ligase alpha subunitpropionyl CoA carboxylase, alpha polypeptidepropionyl Coenzyme A carboxylase, alpha polypeptidepropion
	Modification date	20200313	20200313
	UniProtAcc	Q8N0X4 Main function of 5'-partner protein: FUNCTION: Mitochondrial citramalyl-CoA lyase indirectly involved in the vitamin B12 metabolism (PubMed:29056341). Converts citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway (PubMed:29056341). The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, a vitamin B12-poisoning metabolite (PubMed:29056341). Also acts as a malate synthase in vitro, converting glyoxylate and acetyl-CoA to malate (PubMed:29056341, PubMed:24334609). Also displays malyl-CoA thioesterase activity (PubMed:29056341). Also acts as a beta-methylmalate synthase in vitro, by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate (PubMed:24334609, PubMed:29056341). Also has very weak citramalate synthase activity in vitro (PubMed:24334609, PubMed:29056341). {ECO:0000269\|PubMed:24334609, ECO:0000269\|PubMed:29056341}.	.
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000339105, ENST00000376354, ENST00000376355, ENST00000376360, ENST00000444838,	ENST00000485946, ENST00000376279, ENST00000376285, ENST00000376286,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	7 X 8 X 4=224	21 X 22 X 6=2772
	# samples	8	23
	** MAII score	log2(8/224*10)=-1.48542682717024 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(23/2772*10)=-3.59122149119284 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Fusion gene context	PubMed: CLYBL [Title/Abstract] AND PCCA [Title/Abstract] AND fusion [Title/Abstract]
Fusion neoantigen context	PubMed: CLYBL [Title/Abstract] AND PCCA [Title/Abstract] AND neoantigen [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	PCCA(100921037)-CLYBL(100543572), # samples:3 PCCA(100888132)-CLYBL(100425078), # samples:3 PCCA(100764315)-CLYBL(100425078), # samples:3 CLYBL(100511303)-PCCA(101077887), # samples:1 CLYBL(100433686)-PCCA(100775572), # samples:1
Anticipated loss of major functional domain due to fusion event.	CLYBL-PCCA 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. CLYBL-PCCA 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. CLYBL-PCCA 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. CLYBL-PCCA 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. PCCA-CLYBL seems lost the major protein functional domain in Hgene partner, which is a cell metabolism gene due to the frame-shifted ORF. PCCA-CLYBL seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted 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
Hgene	CLYBL	GO:0070207	protein homotrimerization	29056341
Hgene	CLYBL	GO:0106064	regulation of cobalamin metabolic process	29056341

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr13:100921037/chr13:100543572)
- 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 CLYBL (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 PCCA (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)
ENST00000376355	CLYBL	chr13	100511303	+	ENST00000376279	PCCA	chr13	101077887	+	1035	469	31	768	245
ENST00000376355	CLYBL	chr13	100511303	+	ENST00000376286	PCCA	chr13	101077887	+	1176	469	31	909	292
ENST00000376355	CLYBL	chr13	100511303	+	ENST00000376285	PCCA	chr13	101077887	+	1176	469	31	909	292
ENST00000444838	CLYBL	chr13	100511303	+	ENST00000376279	PCCA	chr13	101077887	+	1031	465	27	764	245
ENST00000444838	CLYBL	chr13	100511303	+	ENST00000376286	PCCA	chr13	101077887	+	1172	465	27	905	292
ENST00000444838	CLYBL	chr13	100511303	+	ENST00000376285	PCCA	chr13	101077887	+	1172	465	27	905	292
ENST00000376360	CLYBL	chr13	100511303	+	ENST00000376279	PCCA	chr13	101077887	+	1031	465	27	764	245
ENST00000376360	CLYBL	chr13	100511303	+	ENST00000376286	PCCA	chr13	101077887	+	1172	465	27	905	292
ENST00000376360	CLYBL	chr13	100511303	+	ENST00000376285	PCCA	chr13	101077887	+	1172	465	27	905	292
ENST00000376354	CLYBL	chr13	100511303	+	ENST00000376279	PCCA	chr13	101077887	+	1010	444	6	743	245
ENST00000376354	CLYBL	chr13	100511303	+	ENST00000376286	PCCA	chr13	101077887	+	1151	444	6	884	292
ENST00000376354	CLYBL	chr13	100511303	+	ENST00000376285	PCCA	chr13	101077887	+	1151	444	6	884	292
ENST00000339105	CLYBL	chr13	100511303	+	ENST00000376279	PCCA	chr13	101077887	+	1004	438	0	737	245
ENST00000339105	CLYBL	chr13	100511303	+	ENST00000376286	PCCA	chr13	101077887	+	1145	438	0	878	292
ENST00000339105	CLYBL	chr13	100511303	+	ENST00000376285	PCCA	chr13	101077887	+	1145	438	0	878	292

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
ENST00000376355	ENST00000376279	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000902565	0.99909747
ENST00000376355	ENST00000376286	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000439325	0.99956065
ENST00000376355	ENST00000376285	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000439325	0.99956065
ENST00000444838	ENST00000376279	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000903489	0.9990965
ENST00000444838	ENST00000376286	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000441961	0.99955803
ENST00000444838	ENST00000376285	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000441961	0.99955803
ENST00000376360	ENST00000376279	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000903489	0.9990965
ENST00000376360	ENST00000376286	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000441961	0.99955803
ENST00000376360	ENST00000376285	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000441961	0.99955803
ENST00000376354	ENST00000376279	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.00091443	0.99908555
ENST00000376354	ENST00000376286	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.00044479	0.9995552
ENST00000376354	ENST00000376285	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.00044479	0.9995552
ENST00000339105	ENST00000376279	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000862706	0.9991373
ENST00000339105	ENST00000376286	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000426759	0.9995733
ENST00000339105	ENST00000376285	CLYBL	chr13	100511303	+	PCCA	chr13	101077887	+	0.000426759	0.9995733

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 CLYBL-PCCA

+/-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 CLYBL-PCCA 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 CLYBL-PCCA 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 CLYBL-PCCA

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 CLYBL-PCCA

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 CLYBL-PCCA

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 CLYBL-PCCA

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 CLYBL-PCCA

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 CLYBL-PCCA

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 CLYBL-PCCA

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)