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	Fusion Gene Summary
	Fusion Gene Sample Information
	Fusion ORF Analysis
	Fusion Amino Acid Sequences
	Fusion Protein Functional Features
	Fusion Protein Structure
	pLDDT scores
	Ramachandran Plot of Fusion Protein Structure
	Fusion Protein-Protein Interaction
	Related drugs with this fusion protein
	Related disease with this fusion protein

Fusion Protein:HADH-NCL

Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: HADH-NCL
	FusionPDB ID: 35586
	FusionGDB2.0 ID: 35586
		Hgene	Tgene
	Gene symbol	HADH	NCL
	Gene ID	3033	80331
	Gene name	hydroxyacyl-CoA dehydrogenase	DnaJ heat shock protein family (Hsp40) member C5
	Synonyms	HAD\|HADH1\|HADHSC\|HCDH\|HHF4\|MSCHAD\|SCHAD	CLN4\|CLN4B\|CSP\|DNAJC5A\|NCL\|mir-941-2\|mir-941-3\|mir-941-4\|mir-941-5
	Cytomap	4q25	20q13.33
	Type of gene	protein-coding	protein-coding
	Description	hydroxyacyl-coenzyme A dehydrogenase, mitochondrialL-3-hydroxyacyl-Coenzyme A dehydrogenase, short chainmedium and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenaseshort-chain 3-hydroxyacyl-CoA dehydrogenasetestis secretory sperm-binding protein Li	dnaJ homolog subfamily C member 5DnaJ (Hsp40) homolog, subfamily C, member 5ceroid-lipofuscinosis neuronal protein 4cysteine string protein alpha
	Modification date	20200320	20200328
	UniProtAcc	P55084	Q969V3
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000510728, ENST00000454409, ENST00000505878, ENST00000603302, ENST00000309522, ENST00000403312,	ENST00000322723,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	7 X 6 X 3=126	20 X 21 X 7=2940
	# samples	7	23
	** MAII score	log2(7/126*10)=-0.84799690655495 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(23/2940*10)=-3.67611038877935 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Context (manual curation of fusion genes in FusionPDB)	PubMed: HADH [Title/Abstract] AND NCL [Title/Abstract] AND fusion [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	HADH(108955491)-NCL(232322411), # samples:2
Anticipated loss of major functional domain due to fusion event.	HADH-NCL 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. HADH-NCL 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. HADH-NCL seems lost the major protein functional domain in Hgene partner, which is a cell metabolism gene due to the frame-shifted ORF. HADH-NCL seems lost the major protein functional domain in Tgene partner, which is a epigenetic factor due to the frame-shifted ORF. HADH-NCL seems lost the major protein functional domain in Tgene partner, which is a essential gene 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

Fusion gene breakpoints across HADH (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 NCL (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 Gene Sample Information

Fusion gene information from FusionGDB2.0.

Fusion gene information from two resources (ChiTars 5.0 and ChimerDB 4.0)
* All genome coordinats were lifted-over on hg19.
* Click on the break point to see the gene structure around the break point region using the UCSC Genome Browser.

Source	Disease	Sample	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand
ChiTaRS5.0	N/A	BF348759	HADH	chr4	108955491	+	NCL	chr2	232322411	-
ChiTaRS5.0	N/A	BQ314823	HADH	chr4	108955491	+	NCL	chr2	232322411	-

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Fusion ORF Analysis

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)

ENST00000403312

HADH

chr4

108955491

ENST00000322723

NCL

chr2

232322411

4340

1936

1139

365

ENST00000309522

HADH

chr4

108955491

ENST00000322723

NCL

chr2

232322411

4219

1815

1018

325

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
ENST00000403312	ENST00000322723	HADH	chr4	108955491	+	NCL	chr2	232322411	-	0.00091144	0.9990885
ENST00000309522	ENST00000322723	HADH	chr4	108955491	+	NCL	chr2	232322411	-	0.00042435	0.9995757

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Fusion Amino Acid Sequences

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

>FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP

>35586_35586_1_HADH-NCL_HADH_chr4_108955491_ENST00000309522_NCL_chr2_232322411_ENST00000322723_length(amino acids)=325AA_BP=
MQGRVGPRPQSLAFRGCPPRASSLPGSPRCRRRCHTMAFVTRQFMRSVSSSSTASASAKKIIVKHVTVIGGGLMGAGIAQVAAATGHTVV
LVDQTEDILAKSKKGIEESLRKVAKKKFAENLKAGDEFVEKTLSTIATSTDAASVVHSTDLVVEAIVENLKVKNELFKRLDKFAAEHTIF
ASNTSSLQITSIANATTRQDRFAGLHFFNPVPVMKLVEVIKTPMTSQKTFESLVDFSKALGKHPVSCKDTPGFIVNRLLVPYLMEAIRLY

--------------------------------------------------------------

>35586_35586_2_HADH-NCL_HADH_chr4_108955491_ENST00000403312_NCL_chr2_232322411_ENST00000322723_length(amino acids)=365AA_BP=
MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLAFRGCPPRASSLPGSPRCRRRCHTMAFVTRQFMRSVSSSSTASASAKKIIVKHVT
VIGGGLMGAGIAQVAAATGHTVVLVDQTEDILAKSKKGIEESLRKVAKKKFAENLKAGDEFVEKTLSTIATSTDAASVVHSTDLVVEAIV
ENLKVKNELFKRLDKFAAEHTIFASNTSSLQITSIANATTRQDRFAGLHFFNPVPVMKLVEVIKTPMTSQKTFESLVDFSKALGKHPVSC
KDTPGFIVNRLLVPYLMEAIRLYERDFQTCGDSNSGLGFSLKGDASKEDIDTAMKLGAGYPMGPFELLDYVGLDTTKFIVDEDFTNTSDV

--------------------------------------------------------------

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Fusion Protein Functional Features

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr4:108955491/chr2:232322411)
- 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.

Main function of each fusion partner protein. (from UniProt)

Hgene	Tgene
HADH P55084	NCL Q969V3
FUNCTION: Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:8135828, PubMed:29915090, PubMed:30850536). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (PubMed:30850536). Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity (PubMed:8135828, PubMed:29915090, PubMed:30850536). {ECO:0000269\|PubMed:29915090, ECO:0000269\|PubMed:30850536, ECO:0000269\|PubMed:8135828, ECO:0000303\|PubMed:29915090, ECO:0000303\|PubMed:30850536}.	FUNCTION: Component of a ribosome-associated translocon complex involved in multi-pass membrane protein transport into the endoplasmic reticulum (ER) membrane and biogenesis (PubMed:32820719). May antagonize Nodal signaling and subsequent organization of axial structures during mesodermal patterning, via its interaction with NOMO (By similarity). {ECO:0000250\|UniProtKB:Q6NZ07, ECO:0000269\|PubMed:32820719}.

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, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at
download page
* Minus value of BPloci means that the break pointn is located before the CDS.

- Retained protein feature among the 13 regional features.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

143_171

711.0

Compositional bias

Note=Asp/Glu-rich (acidic)

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

185_209

711.0

Compositional bias

Note=Asp/Glu-rich (acidic)

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

234_271

711.0

Compositional bias

Note=Asp/Glu-rich (acidic)

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

649_698

711.0

Compositional bias

Note=Arg/Gly/Phe-rich

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

307_383

711.0

Domain

RRM 1

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

393_466

711.0

Domain

RRM 2

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

486_560

711.0

Domain

RRM 3

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

572_647

711.0

Domain

RRM 4

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

58_135

711.0

Region

Note=8 X 8 AA tandem repeats of X-T-P-X-K-K-X-X

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

105_112

711.0

Repeat

Note=6

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

120_127

711.0

Repeat

Note=7

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

128_135

711.0

Repeat

Note=8

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

58_65

711.0

Repeat

Note=1

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

75_82

711.0

Repeat

Note=2

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

83_90

711.0

Repeat

Note=3

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

91_98

711.0

Repeat

Note=4

Tgene

NCL

chr4:108955491

chr2:232322411

ENST00000322723

99_104

711.0

Repeat

Note=5%3B truncated

- Not-retained protein feature among the 13 regional features.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

Hgene

HADH

chr4:108955491

chr2:232322411

ENST00000309522

34_39

315.0

Nucleotide binding

NAD

Hgene

HADH

chr4:108955491

chr2:232322411

ENST00000603302

34_39

332.0

Nucleotide binding

NAD

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Fusion Protein Structures

PDB and CIF files of the predicted fusion proteins
* Here we show the 3D structure of the fusion proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

Fusion protein PDB link (fusion AA seq ID in FusionPDB)	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	AA seq	Len(AA seq)
PDB file >>>719_HADH_108955491_NCL_232322411_ranked_0.pdb	HADH	108955491	108955491	ENST00000322723	NCL	chr2	232322411	-	MGRAGLEAPPPPCGVTGTPGARGLQGRVGPRPQSLAFRGCPPRASSLPGSPRCRRRCHTMAFVTRQFMRSVSSSSTASASAKKIIVKHVT VIGGGLMGAGIAQVAAATGHTVVLVDQTEDILAKSKKGIEESLRKVAKKKFAENLKAGDEFVEKTLSTIATSTDAASVVHSTDLVVEAIV ENLKVKNELFKRLDKFAAEHTIFASNTSSLQITSIANATTRQDRFAGLHFFNPVPVMKLVEVIKTPMTSQKTFESLVDFSKALGKHPVSC KDTPGFIVNRLLVPYLMEAIRLYERDFQTCGDSNSGLGFSLKGDASKEDIDTAMKLGAGYPMGPFELLDYVGLDTTKFIVDEDFTNTSDV	365

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pLDDT score distribution

pLDDT score distribution of the predicted wild-type structures of two partner proteins from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

HADH_pLDDT.png

NCL_pLDDT.png

pLDDT score distribution of the predicted fusion protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

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Ramachandran Plot of Fusion Protein Structure

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this fusion protein peptide.

Fusion AA seq ID in FusionPDB and their Ramachandran plots

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Fusion Protein-Protein Interaction

Go to ChiPPI (Chimeric Protein-Protein interactions) to see the chimeric PPI interaction in
ChiPPI page.

Protein-protein interactors with each fusion partner protein in wild-type from validated records (BIOGRID-3.4.160)

Gene

PPI interactors

Protein-protein interactors based on sequence similarity (STRING)

Gene	STRING network
HADH
NCL

- Retained interactions in fusion protein (protein functional feature from UniProt).

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Still interaction with

- Lost interactions due to fusion (protein functional feature from UniProt).

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Interaction lost with

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Related Drugs to HADH-NCL

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 HADH-NCL

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