ZC3H12D

Summary

ZC3H12D (zinc finger CCCH-type containing 12D, HGNC:21175) is a protein-coding gene on chromosome 6q25.1, encoding Probable ribonuclease ZC3H12D (A2A288). May regulate cell growth likely by suppressing RB1 phosphorylation.

Predicted to enable RNA endonuclease activity and mRNA binding activity. Involved in negative regulation of G1/S transition of mitotic cell cycle and negative regulation of cell growth. Located in P-body and nucleoplasm.

Source: NCBI Gene 340152 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 94 total
• MANE Select transcript: NM_207360

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21175
Approved symbol	ZC3H12D
Name	zinc finger CCCH-type containing 12D
Location	6q25.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ281H8.1, MCPIP4
Ensembl gene	ENSG00000178199
Ensembl biotype	protein_coding
OMIM	611106
Entrez	340152

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000409806, ENST00000409948, ENST00000458251, ENST00000462655, ENST00000498662

RefSeq mRNA: 1 — MANE Select: NM_207360 NM_207360

CCDS: CCDS47500

Canonical transcript exons

ENST00000409806 — 6 exons

Exon	Start	End
ENSE00000813606	149452616	149452722
ENSE00000813607	149456666	149456900
ENSE00000813608	149461831	149461970
ENSE00001578331	149446795	149451479
ENSE00001860500	149484813	149485014
ENSE00003588125	149474239	149474613

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 89.16.

FANTOM5 (CAGE): breadth broad, TPM avg 4.5309 / max 355.7129, expressed in 392 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76125	2.2397	291
76121	0.7321	158
76126	0.7259	187
76123	0.4198	121
76122	0.2590	99
76124	0.1108	62
76120	0.0437	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	89.16	gold quality
superficial temporal artery	UBERON:0001614	84.99	gold quality
lymph node	UBERON:0000029	83.83	gold quality
jejunal mucosa	UBERON:0000399	82.90	gold quality
vermiform appendix	UBERON:0001154	81.76	gold quality
blood	UBERON:0000178	81.25	gold quality
spleen	UBERON:0002106	81.18	gold quality
granulocyte	CL:0000094	81.04	gold quality
tonsil	UBERON:0002372	79.52	gold quality
colonic mucosa	UBERON:0000317	78.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	77.64	gold quality
mucosa of transverse colon	UBERON:0004991	76.33	gold quality
duodenum	UBERON:0002114	76.14	gold quality
caecum	UBERON:0001153	75.26	gold quality
leukocyte	CL:0000738	75.05	gold quality
monocyte	CL:0000576	74.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	74.47	gold quality
bone marrow cell	CL:0002092	74.42	gold quality
thymus	UBERON:0002370	73.81	gold quality
small intestine	UBERON:0002108	73.29	gold quality
bone marrow	UBERON:0002371	71.43	gold quality
germinal epithelium of ovary	UBERON:0001304	70.88	gold quality
palpebral conjunctiva	UBERON:0001812	70.33	gold quality
buccal mucosa cell	CL:0002336	70.15	gold quality
rectum	UBERON:0001052	70.08	gold quality
oviduct epithelium	UBERON:0004804	69.36	gold quality
transverse colon	UBERON:0001157	68.64	gold quality
colonic epithelium	UBERON:0000397	67.40	silver quality
intestine	UBERON:0000160	67.25	gold quality
jejunum	UBERON:0002115	66.84	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	64.85
E-ANND-3	yes	4.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting ZC3H12D, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3617-5P	99.75	69.41	1968

Literature-anchored findings (GeneRIF, showing 6)

• MCPIP1, 2, 3, and 4, encoded by four genes, Zc3h12a, Zc3h12b, Zc3h12c, and Zc3h12d, respectively, regulates macrophage activation. (PMID:18178554)
• Zc3h12d is a novel negative feedback regulator of TLR signaling and macrophage activation and thus may play a role in host immunity and inflammatory diseases. (PMID:22036805)
• The data indicated that ZC3H12D could suppress both the initial inflammation storm and chronic inflammation by targeting the mRNA of cytokines as well as NF-kappaB and c-fos. (PMID:26059755)
• MCPIP1 and MCPIP4 form a complex but they act independently in regulation of IL-6 mRNA degradation. (PMID:26134560)
• overexpression of ZC3H12D increases the turnover rate of transcripts containing ZC3H12A 3’UTR. (PMID:27472830)
• Long non-coding RNA FOXP4-AS1 facilitates the biological functions of hepatocellular carcinoma cells via downregulating ZC3H12D by mediating H3K27me3 through recruitment of EZH2. (PMID:34545456)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zc3h12d	ENSMUSG00000039981
rattus_norvegicus	Zc3h12d	ENSRNOG00000016041
drosophila_melanogaster	Regnase-1	FBGN0038769
drosophila_melanogaster	CG42360	FBGN0259742
caenorhabditis_elegans		WBGENE00013107
caenorhabditis_elegans	rege-1	WBGENE00016260
caenorhabditis_elegans		WBGENE00021287
caenorhabditis_elegans		WBGENE00021998
caenorhabditis_elegans		WBGENE00022003

Paralogs (6): KHNYN (ENSG00000100441), ZC3H12B (ENSG00000102053), N4BP1 (ENSG00000102921), ZC3H12C (ENSG00000149289), ZC3H12A (ENSG00000163874), NYNRIN (ENSG00000205978)

Protein

Protein identifiers

Probable ribonuclease ZC3H12D — A2A288 (reviewed: A2A288)

Alternative names: MCP-induced protein 4, Transformed follicular lymphoma, Zinc finger CCCH domain-containing protein 12D, p34

All UniProt accessions (3): A2A288, B7ZBA4, H0Y4Y6

UniProt curated annotations — full annotation on UniProt →

Function. May regulate cell growth likely by suppressing RB1 phosphorylation. May function as RNase and regulate the levels of target RNA species (Potential). In association with ZC3H12A enhances the degradation of interleukin IL-6 mRNA level in activated macrophages. Serve as a tumor suppressor in certain leukemia cells. Overexpression inhibits the G1 to S phase progression through suppression of RB1 phosphorylation.

Subunit / interactions. Interacts with ZC3H12A.

Subcellular location. Cytoplasm. P-body Cytoplasm Cytoplasm. Nucleus.

Tissue specificity. Expressed in normal human lymphocytes but defective in some leukemia/lymphoma cell lines.

Disease relevance. A chromosomal aberration involving ZC3H12D may be the cause of the transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL). Translocation t(2;6)(p12;q25) with IGK. Resulting protein may not be expressed.

Induction. By prolonged exposure to bacterial lipopolysaccharides (LPS) in acute monocytic leukemia cell line THP-1 cells.

Similarity. Belongs to the ZC3H12 family.

Isoforms (3)

UniProt ID	Names	Canonical?
A2A288-1	1, P58TFL, TFL1	yes
A2A288-3	2
A2A288-4	3, P36TFL, TFL2

RefSeq proteins (1): NP_997243* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000571	Znf_CCCH	Domain
IPR021869	RNase_Zc3h12_NYN	Domain
IPR040546	Rege-1_UBA-like	Domain
IPR051101	ZC3H12/N4BP1_RNase_Reg	Family

Pfam: PF11977, PF18039

UniProt features (24 total): sequence conflict 8, region of interest 5, splice variant 3, sequence variant 2, compositionally biased region 2, chain 1, domain 1, mutagenesis site 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A2A288-F1	70.06	0.37

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
95	inhibits interleukin il6 mrna instability.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 166 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, chr6q25, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE

GO Biological Process (3): negative regulation of cell growth (GO:0030308), 3’-UTR-mediated mRNA destabilization (GO:0061158), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134)

GO Molecular Function (8): mRNA binding (GO:0003729), RNA endonuclease activity (GO:0004521), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoplasmic ribonucleoprotein granule (GO:0036464)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
mRNA destabilization	1
G1/S transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
RNA binding	1
endonuclease activity	1
RNA nuclease activity	1
transition metal ion binding	1
catalytic activity	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
binding	1
cation binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
ribonucleoprotein granule	1

Protein interactions and networks

STRING

494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZC3H12D	CNR2	P34972	899
ZC3H12D	RC3H2	Q9HBD1	497
ZC3H12D	SIDT1	Q9NXL6	475
ZC3H12D	RC3H1	Q5TC82	430
ZC3H12D	BCAS4	Q8TDM0	397
ZC3H12D	RNASE13	Q5GAN3	366
ZC3H12D	LARS1	Q9P2J5	364
ZC3H12D	LURAP1	Q96LR2	355
ZC3H12D	IER3	P46695	349
ZC3H12D	PRSS36	Q5K4E3	348
ZC3H12D	ZFP36	P26651	343
ZC3H12D	TJAP1	Q5JTD0	335
ZC3H12D	CIROZ	Q8N9H9	327
ZC3H12D	CXorf65	A6NEN9	323
ZC3H12D	THOC3	Q96J01	317

IntAct

0 interactions, top by confidence:

BioGRID (6): ZC3H12D (Affinity Capture-MS), ZC3H12D (Affinity Capture-Western), ZC3H12A (Affinity Capture-Western), ZC3H12D (Two-hybrid), ZC3H12A (Two-hybrid), ZC3H12D (Affinity Capture-RNA)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: A0JPN4, A2A288, A6QQJ8, O15037, O75113, Q1LVK9, Q5D1E7, Q5D1E8, Q5DTV4, Q5DTZ0, Q5HYM0, Q5ZLE9, Q6A037, Q6DJS0, Q7ZXG4, Q80U38, Q8BIY3, Q95YE2, Q9C0D7, Q9P2P1, A6NKG5, Q8I7P9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

878 predictions. Top by Δscore:

Variant	Effect	Δscore
6:149452658:T:TA	donor_gain	1.0000
6:149456664:A:AC	donor_gain	1.0000
6:149456665:C:CC	donor_gain	1.0000
6:149456665:C:G	donor_loss	1.0000
6:149456665:CCGGT:C	donor_gain	1.0000
6:149452612:CCAC:C	donor_loss	0.9900
6:149452613:CAC:C	donor_loss	0.9900
6:149452614:A:AG	donor_loss	0.9900
6:149452615:C:CG	donor_loss	0.9900
6:149456665:CCGG:C	donor_gain	0.9900
6:149456715:T:TA	donor_gain	0.9900
6:149456896:CTGCT:C	acceptor_gain	0.9900
6:149456899:CT:C	acceptor_gain	0.9900
6:149456901:C:A	acceptor_gain	0.9900
6:149456901:C:CC	acceptor_gain	0.9900
6:149461968:TGG:T	acceptor_gain	0.9900
6:149461971:C:CC	acceptor_gain	0.9900
6:149474610:TGAG:T	acceptor_gain	0.9900
6:149474614:C:CC	acceptor_gain	0.9900
6:149484809:TCACC:T	donor_loss	0.9900
6:149484810:CACCA:C	donor_loss	0.9900
6:149484811:A:AC	donor_gain	0.9900
6:149484811:ACC:A	donor_loss	0.9900
6:149484812:C:CC	donor_gain	0.9900
6:149484812:CCAG:C	donor_gain	0.9900
6:149450660:C:A	donor_gain	0.9800
6:149452718:TGAAC:T	acceptor_gain	0.9800
6:149452720:AACC:A	acceptor_loss	0.9800
6:149452722:CCTGG:C	acceptor_loss	0.9800
6:149452723:C:CA	acceptor_loss	0.9800

AlphaMissense

3399 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:149452720:A:G	F228S	1.000
6:149456718:A:G	W210R	1.000
6:149456718:A:T	W210R	1.000
6:149456753:T:A	D198V	1.000
6:149456753:T:G	D198A	1.000
6:149456759:G:A	S196F	1.000
6:149456762:A:T	V195D	1.000
6:149456807:T:A	D180V	1.000
6:149456807:T:C	D180G	1.000
6:149456807:T:G	D180A	1.000
6:149461865:C:A	R137S	1.000
6:149461865:C:G	R137S	1.000
6:149461878:A:T	V133D	1.000
6:149461949:G:C	F109L	1.000
6:149461949:G:T	F109L	1.000
6:149461951:A:G	F109L	1.000
6:149451439:G:C	H276Q	0.999
6:149451439:G:T	H276Q	0.999
6:149451441:G:C	H276D	0.999
6:149451445:G:C	F274L	0.999
6:149451445:G:T	F274L	0.999
6:149451447:A:G	F274L	0.999
6:149451451:G:C	C272W	0.999
6:149451452:C:A	C272F	0.999
6:149451452:C:G	C272S	0.999
6:149451453:A:G	C272R	0.999
6:149451453:A:T	C272S	0.999
6:149451469:G:C	C266W	0.999
6:149451470:C:G	C266S	0.999
6:149451471:A:G	C266R	0.999

dbSNP variants (sampled 300 via entrez): RS1000077666 (6:149484061 G>A), RS1000181794 (6:149484372 A>G), RS1000185101 (6:149480791 G>A,T), RS1000214336 (6:149481116 C>G,T), RS1000311389 (6:149446731 G>T), RS1000343626 (6:149446513 C>A), RS1000402647 (6:149473858 G>C,T), RS1000503404 (6:149452089 C>G), RS1000585728 (6:149480420 T>C), RS1000604293 (6:149458703 G>T), RS1000638469 (6:149459073 T>C), RS1000654024 (6:149478881 G>A), RS1000766864 (6:149464576 G>A), RS1000827280 (6:149475203 C>T), RS1000848886 (6:149469329 G>A,T)

Disease associations

OMIM: gene MIM:611106 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001144_2	Dupuytren’s disease	3.000000e-07
GCST004858_4	Dupuytren’s disease	1.000000e-17
GCST010042_80	Asthma	3.000000e-09
GCST010043_150	Asthma	2.000000e-10
GCST90002381_167	Eosinophil count	1.000000e-09
GCST90002382_358	Eosinophil percentage of white cells	2.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004229	Dupuytren Contracture
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, affects methylation, decreases methylation	1
aflatoxin B2	decreases methylation	1
15-acetyldeoxynivalenol	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Nickel	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Serpentine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2PK	HAP1 ZC3H12D (-) 1	Cancer cell line	Male
CVCL_E2PL	HAP1 ZC3H12D (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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