TSSC4

Summary

TSSC4 (tumor suppressing subtransferable candidate 4, HGNC:12386) is a protein-coding gene on chromosome 11p15.5, encoding U5 small nuclear ribonucleoprotein TSSC4 (Q9Y5U2). Protein associated with the U5 snRNP, during its maturation and its post-splicing recycling and which is required for spliceosomal tri-snRNP complex assembly in the nucleus.

This gene is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. This gene is located among several imprinted genes; however, this gene, as well as the pan-hematopoietic expression gene (PHEMX), escapes imprinting. This gene may play a role in malignancies and disease that involve this region. Several transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 10078 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_005706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12386
Approved symbol	TSSC4
Name	tumor suppressing subtransferable candidate 4
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184281
Ensembl biotype	protein_coding
OMIM	603852
Entrez	10078

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 21 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000333256, ENST00000380992, ENST00000380996, ENST00000435795, ENST00000437110, ENST00000440813, ENST00000451491, ENST00000467308, ENST00000485682, ENST00000496468, ENST00000867309, ENST00000867310, ENST00000867311, ENST00000867312, ENST00000867313, ENST00000867314, ENST00000867315, ENST00000920269, ENST00000920270, ENST00000920271, ENST00000954227, ENST00000954228

RefSeq mRNA: 5 — MANE Select: NM_005706 NM_001297658, NM_001297659, NM_001297660, NM_001297661, NM_005706

CCDS: CCDS73241, CCDS7735

Canonical transcript exons

ENST00000333256 — 3 exons

Exon	Start	End
ENSE00001326678	2402611	2403876
ENSE00001375188	2402294	2402450
ENSE00001487231	2400750	2400798

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 95.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.0618 / max 106.9074, expressed in 1803 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112699	15.0618	1803

Top tissues by expression

272 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	95.86	gold quality
right testis	UBERON:0004534	95.54	gold quality
apex of heart	UBERON:0002098	93.81	gold quality
granulocyte	CL:0000094	93.75	gold quality
testis	UBERON:0000473	93.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.30	gold quality
left uterine tube	UBERON:0001303	93.14	gold quality
lower esophagus mucosa	UBERON:0035834	93.05	gold quality
gastrocnemius	UBERON:0001388	92.77	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.54	gold quality
lower esophagus	UBERON:0013473	92.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.28	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.22	gold quality
muscle of leg	UBERON:0001383	91.85	gold quality
body of uterus	UBERON:0009853	91.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.75	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.56	gold quality
popliteal artery	UBERON:0002250	91.43	gold quality
tibial artery	UBERON:0007610	91.43	gold quality
mucosa of transverse colon	UBERON:0004991	91.23	gold quality
aorta	UBERON:0000947	91.05	gold quality
left coronary artery	UBERON:0001626	91.03	gold quality
ascending aorta	UBERON:0001496	90.85	gold quality
thoracic aorta	UBERON:0001515	90.82	gold quality
adenohypophysis	UBERON:0002196	90.71	gold quality
body of stomach	UBERON:0001161	90.61	gold quality
mucosa of stomach	UBERON:0001199	90.52	gold quality
skin of leg	UBERON:0001511	90.49	gold quality
upper lobe of left lung	UBERON:0008952	90.34	gold quality
right lobe of liver	UBERON:0001114	90.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting TSSC4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-6753-5P	94.70	64.08	470

Literature-anchored findings (GeneRIF, showing 2)

• TSSC4 gene, located in the center of the 11p15 imprinted region, escapes genomic imprinting. (PMID:10072438)
• TSSC4 is a component of U5 snRNP that promotes tri-snRNP formation. (PMID:34131137)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tssc4	ENSDARG00000036144
mus_musculus	Tssc4	ENSMUSG00000045752
rattus_norvegicus	Tssc4	ENSRNOG00000032677
drosophila_melanogaster	CG6674	FBGN0036063

Protein

Protein identifiers

U5 small nuclear ribonucleoprotein TSSC4 — Q9Y5U2 (reviewed: Q9Y5U2)

Alternative names: Tumor-suppressing STF cDNA 4 protein, Tumor-suppressing subchromosomal transferable fragment candidate gene 4 protein

All UniProt accessions (7): A6NCC9, C9JDU0, C9JHT9, Q9Y5U2, C9JJV1, E9PL88, E9PME3

UniProt curated annotations — full annotation on UniProt →

Function. Protein associated with the U5 snRNP, during its maturation and its post-splicing recycling and which is required for spliceosomal tri-snRNP complex assembly in the nucleus. Has a molecular sequestering activity and transiently hinders SNRNP200 binding sites for constitutive splicing factors that intervene later during the assembly of the spliceosome and splicing. Together with its molecular sequestering activity, may also function as a molecular adapter and placeholder, coordinating the assembly of the U5 snRNP and its association with the U4/U6 di-snRNP.

Subunit / interactions. Interacts in a RNA-independent manner with distinct U5 snRNP-containing complexes, the mono-U5 snRNP and the post-splicing U5 snRNP-PRPF19 complex. Interacts with SNRNP200; the interaction is direct, excludes recruitment of C9ORF78 and WBP4 to SNRNP200 and negatively regulates its RNA helicase activity. Interacts with PRPF8; the interaction is direct.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in fetal brain, lung, liver and kidney. Widely expressed in adult tissues.

Similarity. Belongs to the TSSC4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5U2-1	1	yes
Q9Y5U2-2	2

RefSeq proteins (5): NP_001284587, NP_001284588, NP_001284589, NP_001284590, NP_005697* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029338	TSSC4	Family

Pfam: PF15264

UniProt features (38 total): modified residue 9, region of interest 7, mutagenesis site 6, sequence variant 5, helix 2, turn 2, strand 2, compositionally biased region 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7PX3	ELECTRON MICROSCOPY	3.05
8Q7Q	ELECTRON MICROSCOPY	3.2
8Q7V	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5U2-F1	60.06	0.05

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (9): 60, 67, 86, 132, 143, 146, 217, 265, 321

Mutagenesis-validated functional residues (6):

Position	Phenotype
162	loss of interaction with prpf8 and snrnp200; when associated with a-165, a-201, a-202, a-315 and a-316.
165	loss of interaction with prpf8 and snrnp200; when associated with a-162, a-201, a-202, a-315 and a-316.
201	loss of interaction with snrnp200; when associated with a-202, a-315 and a-316. loss of interaction with prpf8 and snrnp
202	loss of interaction with snrnp200; when associated with a-201, a-315 and a-316. loss of interaction with prpf8 and snrnp
315	loss of interaction with snrnp200; when associated with a-201, a-202 and a-316. loss of interaction with prpf8 and snrnp
316	loss of interaction with snrnp200; when associated with a-201, a-202 and a-315. loss of interaction with prpf8 and snrnp

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): GOBP_SPLICEOSOMAL_TRI_SNRNP_COMPLEX_ASSEMBLY, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, LIAO_METASTASIS, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GOBP_SPLICEOSOMAL_SNRNP_ASSEMBLY, GOCC_U5_SNRNP, GOCC_SPLICEOSOMAL_COMPLEX, GOCC_RIBONUCLEOPROTEIN_COMPLEX, TOOKER_GEMCITABINE_RESISTANCE_UP, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_DN, GOBP_MRNA_PROCESSING, BRIDEAU_IMPRINTED_GENES, GOCC_SM_LIKE_PROTEIN_FAMILY_COMPLEX, GOMF_PROTEIN_CONTAINING_COMPLEX_BINDING

GO Biological Process (4): spliceosomal tri-snRNP complex assembly (GO:0000244), spliceosomal snRNP assembly (GO:0000387), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (3): protein-containing complex binding (GO:0044877), molecular sequestering activity (GO:0140313), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), spliceosomal complex (GO:0005681), U5 snRNP (GO:0005682), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
binding	2
spliceosomal snRNP assembly	1
mRNA splicing, via spliceosome	1
protein-RNA complex assembly	1
mRNA metabolic process	1
molecular_function	1
intracellular membrane-bounded organelle	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
spliceosomal snRNP complex	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSSC4	TSPAN32	Q96QS1	927
TSSC4	PHLDA2	Q53GA4	883
TSSC4	SLC67A1	Q96BI1	831
TSSC4	KCNQ1	P51787	818
TSSC4	TRPM5	Q9NZQ8	781
TSSC4	ASCL2	Q99929	780
TSSC4	CDKN1C	P49918	724
TSSC4	CD81	P18582	705
TSSC4	OSBPL5	Q9H0X9	702
TSSC4	NAP1L4	Q99733	600
TSSC4	SNRPN	P14648	577
TSSC4	IGF2	P01344	553
TSSC4	CEP76	Q8TAP6	549
TSSC4	EHMT2	Q96KQ7	532
TSSC4	AAR2	Q9Y312	532

IntAct

77 interactions, top by confidence:

A	B	Type	Score
SNRPF	GEMIN2	psi-mi:“MI:0914”(association)	0.910
LMO1	ZBTB43	psi-mi:“MI:0914”(association)	0.830
SNRPE	GEMIN2	psi-mi:“MI:0914”(association)	0.770
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
SNRPG	GEMIN2	psi-mi:“MI:0914”(association)	0.710
KPNA3	TSSC4	psi-mi:“MI:0915”(physical association)	0.670
CEP76	TSSC4	psi-mi:“MI:0915”(physical association)	0.670
SNRPB	PRMT5	psi-mi:“MI:0914”(association)	0.670
TSSC4	KPNA3	psi-mi:“MI:0915”(physical association)	0.670
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
DDX23	PRPF4	psi-mi:“MI:0914”(association)	0.640
EFTUD2	SART1	psi-mi:“MI:0914”(association)	0.610
REL	TSSC4	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	TSSC4	psi-mi:“MI:0915”(physical association)	0.560
TSSC4	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
TRAF1	TSSC4	psi-mi:“MI:0915”(physical association)	0.560
FLJ13057	TSSC4	psi-mi:“MI:0915”(physical association)	0.560
TSSC4	RNF31	psi-mi:“MI:0915”(physical association)	0.560
TSSC4	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
TSSC4	TRAF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (248): TSSC4 (Two-hybrid), TSSC4 (Two-hybrid), TSSC4 (Two-hybrid), TSSC4 (Two-hybrid), TSSC4 (Two-hybrid), TSSC4 (Two-hybrid), RNF31 (Two-hybrid), GMCL1 (Two-hybrid), CEP76 (Two-hybrid), IK (Affinity Capture-MS), SNRNP40 (Affinity Capture-MS), PRPF6 (Affinity Capture-MS), SNRNP200 (Affinity Capture-MS), PRPF8 (Affinity Capture-MS), TFIP11 (Affinity Capture-MS)

ESM2 similar proteins: A2A9T0, A2AI08, A4IFI1, A6NCL7, A7MCY6, B0BN13, C9JLW8, D4AE48, P07516, Q0II70, Q0X0E2, Q14DQ1, Q16626, Q1LZD3, Q3LUD4, Q3SZL6, Q3TVI4, Q3U0L2, Q4KLY2, Q4R992, Q5FVH7, Q5JTD0, Q5JXC2, Q5T7N3, Q5XHX2, Q5XIB1, Q5ZIU1, Q60829, Q64327, Q6DG50, Q6J4I0, Q6P9J5, Q6PJ61, Q6ZVH7, Q7TNF9, Q8BG80, Q8CD60, Q8IWY9, Q8NFW9, Q91YU6

Diamond homologs: Q0P4A6, Q1LZD3, Q5XIB1, Q9JHE7, Q9Y5U2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metabolism of non-coding RNA	5	83.5×	2e-07
mRNA Splicing - Minor Pathway	7	41.2×	3e-08
snRNP Assembly	6	33.4×	1e-06
SARS-CoV-2 modulates host translation machinery	5	29.5×	1e-05
mRNA Splicing	7	20.2×	1e-06
CHD1 and CHD2 subfamily	6	17.2×	2e-05
mRNA Splicing - Major Pathway	11	15.8×	1e-08
SARS-CoV-2-host interactions	5	15.7×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal snRNP assembly	7	81.3×	7e-10
mRNA splicing, via spliceosome	11	20.1×	9e-10
RNA splicing	7	12.3×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

70 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

564 predictions. Top by Δscore:

Variant	Effect	Δscore
11:2400795:GCCG:G	donor_gain	0.9900
11:2400797:CGGTA:C	donor_loss	0.9900
11:2400798:GG:G	donor_loss	0.9900
11:2400799:G:GG	donor_gain	0.9900
11:2400799:GTAG:G	donor_loss	0.9900
11:2400800:T:A	donor_loss	0.9900
11:2402762:TGCTG:T	donor_gain	0.9900
11:2402772:G:GT	donor_gain	0.9900
11:2401292:G:GT	donor_gain	0.9800
11:2402283:C:G	acceptor_gain	0.9800
11:2402292:A:AG	acceptor_gain	0.9800
11:2402293:G:GA	acceptor_gain	0.9800
11:2402446:GAGAG:G	donor_gain	0.9800
11:2402448:GAGG:G	donor_loss	0.9800
11:2402449:AGG:A	donor_loss	0.9800
11:2402451:GT:G	donor_loss	0.9800
11:2402452:T:G	donor_loss	0.9800
11:2402605:GTTTA:G	acceptor_loss	0.9800
11:2402606:TTTAG:T	acceptor_loss	0.9800
11:2402607:TTAGG:T	acceptor_loss	0.9800
11:2402608:TAGGT:T	acceptor_loss	0.9800
11:2402609:AGGTG:A	acceptor_loss	0.9800
11:2402610:G:A	acceptor_loss	0.9800
11:2402760:G:GA	donor_gain	0.9800
11:2402282:A:AG	acceptor_gain	0.9700
11:2402286:A:AG	acceptor_gain	0.9700
11:2402293:GTT:G	acceptor_gain	0.9700
11:2402448:GAG:G	donor_gain	0.9700
11:2402610:GGT:G	acceptor_gain	0.9700
11:2401288:G:GT	donor_gain	0.9600

AlphaMissense

2121 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:2403117:T:A	W162R	0.994
11:2403117:T:C	W162R	0.994
11:2403119:G:C	W162C	0.994
11:2403119:G:T	W162C	0.994
11:2402898:T:C	F89L	0.992
11:2402900:C:A	F89L	0.992
11:2402900:C:G	F89L	0.992
11:2402922:T:C	F97L	0.990
11:2402924:T:A	F97L	0.990
11:2402924:T:G	F97L	0.990
11:2403276:T:C	F215L	0.989
11:2403277:T:C	F215S	0.989
11:2403278:C:A	F215L	0.989
11:2403278:C:G	F215L	0.989
11:2402871:T:C	F80L	0.987
11:2402873:C:A	F80L	0.987
11:2402873:C:G	F80L	0.987
11:2403543:T:C	F304L	0.987
11:2403545:C:A	F304L	0.987
11:2403545:C:G	F304L	0.987
11:2403118:G:C	W162S	0.985
11:2403126:T:C	Y165H	0.983
11:2402910:A:C	S93R	0.981
11:2402912:C:A	S93R	0.981
11:2402912:C:G	S93R	0.981
11:2403127:A:C	Y165S	0.979
11:2402899:T:C	F89S	0.976
11:2402923:T:G	F97C	0.974
11:2403115:G:C	R161P	0.973
11:2402899:T:G	F89C	0.970

dbSNP variants (sampled 300 via entrez): RS1000269318 (11:2403152 C>T), RS1000817165 (11:2399161 G>T), RS1000878039 (11:2398996 C>G,T), RS1001058295 (11:2404310 C>T), RS1001291336 (11:2400797 C>G,T), RS1001406944 (11:2401118 G>A), RS1001687541 (11:2399750 C>A), RS1002321380 (11:2402403 T>C), RS1002599766 (11:2401529 G>A,C), RS1003078963 (11:2402031 A>G,T), RS1003693894 (11:2399315 GT>G), RS1003895278 (11:2401083 C>T), RS1005571517 (11:2400259 T>C,G), RS1005751469 (11:2399068 C>T), RS1005865316 (11:2402471 G>A)

Disease associations

OMIM: gene MIM:603852 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects acetylation, affects methylation, increases expression	3
bisphenol A	affects expression, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression, increases expression	1
benzo(e)pyrene	decreases methylation	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
monomethylarsonous acid	affects methylation, affects acetylation	1
abrine	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Atrazine	decreases expression	1
Cisplatin	decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Methapyrilene	decreases methylation	1
Ozone	increases abundance, affects expression	1
Phenobarbital	affects expression	1
Selenium	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.