MS4A3

Summary

MS4A3 (membrane spanning 4-domains A3, HGNC:7317) is a protein-coding gene on chromosome 11q12.1, encoding Membrane-spanning 4-domains subfamily A member 3 (Q96HJ5). Hematopoietic modulator for the G1-S cell cycle transition.

This gene encodes a member of the membrane-spanning 4A gene family. Members of this protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This family member likely plays a role in signal transduction and may function as a subunit associated with receptor complexes. The gene encoding this protein is localized to 11q12, among a cluster of related family members. Alternative splicing may result in multiple transcript variants; however, not all variants have been fully described.

Source: NCBI Gene 932 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 39 total
• MANE Select transcript: NM_006138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7317
Approved symbol	MS4A3
Name	membrane spanning 4-domains A3
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	HTM4
Ensembl gene	ENSG00000149516
Ensembl biotype	protein_coding
OMIM	606498
Entrez	932

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000278865, ENST00000358152, ENST00000395032, ENST00000525686, ENST00000526199, ENST00000528298, ENST00000528952

RefSeq mRNA: 3 — MANE Select: NM_006138 NM_001031666, NM_001031809, NM_006138

CCDS: CCDS31567, CCDS31568, CCDS41651

Canonical transcript exons

ENST00000278865 — 7 exons

Exon	Start	End
ENSE00001681601	60062468	60062605
ENSE00002165704	60070204	60071115
ENSE00002176215	60056665	60056740
ENSE00003461662	60064262	60064318
ENSE00003464891	60061146	60061316
ENSE00003528677	60066951	60067112
ENSE00003537274	60069574	60069675

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 98.07.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.3288 / max 2814.6072, expressed in 122 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114428	6.5665	119
114427	0.6875	53
114426	0.0748	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow	UBERON:0002371	98.07	gold quality
bone marrow cell	CL:0002092	96.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.85	gold quality
monocyte	CL:0000576	88.74	gold quality
leukocyte	CL:0000738	87.31	gold quality
blood	UBERON:0000178	82.30	gold quality
granulocyte	CL:0000094	68.95	gold quality
spleen	UBERON:0002106	68.47	gold quality
right lung	UBERON:0002167	65.67	gold quality
placenta	UBERON:0001987	61.24	gold quality
vermiform appendix	UBERON:0001154	60.11	gold quality
upper lobe of left lung	UBERON:0008952	57.01	gold quality
lung	UBERON:0002048	54.66	gold quality
gall bladder	UBERON:0002110	52.97	gold quality
left testis	UBERON:0004533	51.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	50.88	gold quality
testis	UBERON:0000473	50.73	gold quality
right lobe of liver	UBERON:0001114	50.40	gold quality
duodenum	UBERON:0002114	49.98	gold quality
mucosa of transverse colon	UBERON:0004991	49.81	gold quality
mucosa of stomach	UBERON:0001199	49.69	gold quality
right testis	UBERON:0004534	49.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	48.87	silver quality
liver	UBERON:0002107	47.62	gold quality
lower esophagus mucosa	UBERON:0035834	47.52	silver quality
descending thoracic aorta	UBERON:0002345	47.21	gold quality
adrenal tissue	UBERON:0018303	45.91	silver quality
right coronary artery	UBERON:0001625	45.39	gold quality
endometrium	UBERON:0001295	44.51	silver quality
urinary bladder	UBERON:0001255	44.42	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	2783.64
E-GEOD-89232	yes	1197.17
E-MTAB-9067	yes	1144.09
E-MTAB-10042	yes	486.68
E-CURD-55	yes	414.13
E-HCAD-6	yes	403.71
E-GEOD-100618	yes	345.15
E-MTAB-10432	yes	265.47
E-HCAD-32	yes	70.76
E-CURD-122	yes	12.10
E-HCAD-10	yes	10.28
E-MTAB-9801	yes	7.41
E-ANND-3	no	1.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MZF1

miRNA regulators (miRDB)

65 targeting MS4A3, 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-4682	100.00	68.89	1258
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-185-5P	99.35	68.60	2497

Literature-anchored findings (GeneRIF, showing 7)

• HTm4 binding to KAP.Cdk2.cyclin A complex enhances the phosphatase activity of KAP, dissociates cyclin A, and facilitates KAP dephosphorylation of Cdk2 (PMID:15671017)
• The C-terminal domain is important for the function of HTm4 in cell cycle regulation. (PMID:15830103)
• High HTm4 is associated with neoplasms. (PMID:19818099)
• Our data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness. (PMID:25886616)
• a 7-gene signature was identified which correctly predicted the primary prefibrotic myelofibrosis group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8 (PMID:27579896)
• These results suggest that cell surface expression of MS4A3 is useful to distinguish granulocyte/macrophage lineage-committed progenitors from other lineage-related ones in early human hematopoiesis. In conclusion, MS4A3 is useful to monitor early stage of myeloid differentiation in human hematopoiesis. (PMID:29274779)
• MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common beta-chain cytokine receptor endocytosis. (PMID:34780648)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ms4a3	ENSMUSG00000024681
rattus_norvegicus	Ms4a3	ENSRNOG00000036625

Paralogs (16): MS4A12 (ENSG00000071203), MS4A6A (ENSG00000110077), MS4A4A (ENSG00000110079), MS4A2 (ENSG00000149534), MS4A1 (ENSG00000156738), MS4A6E (ENSG00000166926), MS4A7 (ENSG00000166927), MS4A14 (ENSG00000166928), MS4A5 (ENSG00000166930), MS4A8 (ENSG00000166959), MS4A15 (ENSG00000166961), MS4A10 (ENSG00000172689), TMEM212 (ENSG00000186329), MS4A13 (ENSG00000204979), MS4A18 (ENSG00000214782), MS4A4E (ENSG00000214787)

Protein

Protein identifiers

Membrane-spanning 4-domains subfamily A member 3 — Q96HJ5 (reviewed: Q96HJ5)

Alternative names: CD20 antigen-like protein, Hematopoietic-specific transmembrane protein 4

All UniProt accessions (2): Q96HJ5, E9PRW8

UniProt curated annotations — full annotation on UniProt →

Function. Hematopoietic modulator for the G1-S cell cycle transition. Modulates the level of phosphorylation of cyclin-dependent kinase 2 (CDK2) through its direct binding to cyclin-dependent kinase inhibitor 3 (CDKN3/KAP).

Subunit / interactions. Interacts with CDKN3. Interacts with CDKN3-CDK2 complexes through its binding to CDKN3; this interaction facilitates dissociation of cyclin A from CDKN3-CDK2 complexes.

Subcellular location. Endomembrane system. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed specifically in hematopoietic cells and tissues.

Domain organisation. The C-terminal region is required for binding to CDKN3-CDK2 complexes and the modulation of CDKN3 activity.

Similarity. Belongs to the MS4A family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96HJ5-1	1	yes
Q96HJ5-2	2
Q96HJ5-3	3

RefSeq proteins (3): NP_001026836, NP_001026979, NP_006129* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007237	CD20-like_TM	Domain
IPR030417	MS4A	Family

Pfam: PF04103

UniProt features (16 total): topological domain 5, transmembrane region 4, sequence conflict 3, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HJ5-F1	77.75	0.41

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 102 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, WANG_IMMORTALIZED_BY_HOXA9_AND_MEIS1_UP, GUTIERREZ_WALDENSTROEMS_MACROGLOBULINEMIA_2, GOCC_SECRETORY_VESICLE, GOCC_SPECIFIC_GRANULE, GOCC_SECRETORY_GRANULE_MEMBRANE, KRIGE_RESPONSE_TO_TOSEDOSTAT_6HR_DN, CHYLA_CBFA2T3_TARGETS_UP, WIERENGA_STAT5A_TARGETS_DN, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, GENTLES_LEUKEMIC_STEM_CELL_DN, DUNNE_TARGETS_OF_AML1_MTG8_FUSION_UP, GOCC_SPECIFIC_GRANULE_MEMBRANE

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), specific granule membrane (GO:0035579), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	1
membrane	1
cell periphery	1
secretory granule membrane	1
specific granule	1
cytoplasm	1
intracellular anatomical structure	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

554 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MS4A3	MS4A1	P08984	949
MS4A3	MS4A6E	Q96DS6	507
MS4A3	OR1Q1	Q15612	491
MS4A3	TCN1	P20061	446
MS4A3	MS4A10	Q96PG2	445
MS4A3	RNASE2	P10153	397
MS4A3	SERPINA10	Q9UK55	389
MS4A3	GBP6	Q6ZN66	388
MS4A3	TBX22	Q9Y458	387
MS4A3	ANKRD63	C9JTQ0	385
MS4A3	PDE1B	Q01064	383
MS4A3	DEFA4	P12838	370
MS4A3	BOK	Q9UMX3	369
MS4A3	MS4A7	Q9GZW8	360
MS4A3	SCIMP	Q6UWF3	357

IntAct

122 interactions, top by confidence:

A	B	Type	Score
MS4A3	SLC22A14	psi-mi:“MI:0915”(physical association)	0.600
MS4A3	TEX264	psi-mi:“MI:0915”(physical association)	0.600
MS4A3	STX8	psi-mi:“MI:0915”(physical association)	0.560
MS4A3	SMCO4	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
CLDN1	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
VKORC1L1	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
TMEM182	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
TM4SF18	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
TMEM107	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
TMEM239	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
BNIP3	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
CD53	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
MS4A13	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
MS4A3	TMEM140	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
EFNA5	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
MS4A3	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
YIPF6	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
PLPP6	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
MS4A3	SMIM3	psi-mi:“MI:0915”(physical association)	0.560
CLDN6	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
SGTA	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
MS4A3	SLC5A4	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
NKG7	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	MS4A3	psi-mi:“MI:0915”(physical association)	0.560
ARLN	MS4A3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (40): MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid), MS4A3 (Two-hybrid)

ESM2 similar proteins: A4IIU3, A6NML5, D3YWQ9, O75204, P0DP42, P11836, P20490, P56749, Q01362, Q0IIL2, Q2KJ11, Q2YDM3, Q32KQ5, Q3T110, Q3YBM2, Q497B3, Q4G068, Q504G0, Q5EB63, Q5FWC3, Q5HYL7, Q5M962, Q5R8D6, Q5R9K1, Q5RCD5, Q5RFC1, Q6GV28, Q7T392, Q7TQI0, Q7YQI4, Q8BGP5, Q8BHH8, Q8C6V3, Q8K177, Q8NCR9, Q8VHW1, Q8WXS4, Q920C4, Q925D4, Q940P5

Diamond homologs: A6QPF4, P13386, P20490, Q01362, Q3C1V0, Q3UPL6, Q8N5U1, Q920C4, Q96HJ5, Q96JA4, Q96JQ5, Q99N05, Q99N07, Q99N08, Q99N09, Q99N10, Q9BY19, Q9NXJ0, Q3C2E2, Q5REZ6, Q96PG2, Q9GZW8, Q9H3V2, Q9H2W1, P11836, P19437, Q96PG1, Q96DS6, Q2YDM3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

967 predictions. Top by Δscore:

Variant	Effect	Δscore
11:60061550:GAATA:G	donor_gain	0.9900
11:60061555:G:GG	donor_gain	0.9900
11:60062602:GTTT:G	donor_gain	0.9900
11:60062606:G:GG	donor_gain	0.9900
11:60066526:GATTT:G	donor_gain	0.9900
11:60067113:G:GG	donor_gain	0.9900
11:60069530:T:TA	acceptor_gain	0.9900
11:60069531:G:A	acceptor_gain	0.9900
11:60056737:CAAG:C	donor_loss	0.9800
11:60056740:GGTA:G	donor_loss	0.9800
11:60056741:G:A	donor_loss	0.9800
11:60056742:T:G	donor_loss	0.9800
11:60061145:GCC:G	acceptor_gain	0.9800
11:60061145:GCCAT:G	acceptor_gain	0.9800
11:60062466:A:AG	acceptor_gain	0.9800
11:60062467:G:GG	acceptor_gain	0.9800
11:60064260:A:AG	acceptor_gain	0.9800
11:60064261:G:GG	acceptor_gain	0.9800
11:60062462:TTTCA:T	acceptor_loss	0.9700
11:60062463:TTCA:T	acceptor_loss	0.9700
11:60062464:TCAG:T	acceptor_loss	0.9700
11:60062466:A:C	acceptor_loss	0.9700
11:60062467:G:GC	acceptor_loss	0.9700
11:60064261:GTTCT:G	acceptor_gain	0.9700
11:60067110:AAT:A	donor_gain	0.9700
11:60067111:AT:A	donor_gain	0.9700
11:60061435:T:TA	acceptor_gain	0.9600
11:60062467:GGCC:G	acceptor_gain	0.9600
11:60064251:T:G	acceptor_gain	0.9600
11:60064256:A:AG	acceptor_gain	0.9600

AlphaMissense

1376 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:60066981:A:C	S128R	0.982
11:60066983:T:A	S128R	0.982
11:60066983:T:G	S128R	0.982
11:60062591:T:A	W94R	0.961
11:60062591:T:C	W94R	0.961
11:60062582:T:G	Y91D	0.953
11:60064262:T:C	F99L	0.950
11:60064264:C:A	F99L	0.950
11:60064264:C:G	F99L	0.950
11:60062594:G:C	G95R	0.947
11:60067002:G:T	G135W	0.945
11:60064265:T:C	C100R	0.941
11:60062595:G:A	G95D	0.939
11:60067002:G:A	G135R	0.938
11:60067002:G:C	G135R	0.938
11:60062507:G:C	G66R	0.932
11:60062508:G:A	G66D	0.928
11:60062582:T:C	Y91H	0.926
11:60066994:C:A	A132E	0.923
11:60064268:A:C	S101R	0.920
11:60064270:T:A	S101R	0.920
11:60064270:T:G	S101R	0.920
11:60064275:G:A	G103E	0.917
11:60062487:C:A	A59E	0.915
11:60062580:G:A	G90D	0.914
11:60067003:G:A	G135E	0.908
11:60061314:G:T	G52W	0.904
11:60061314:G:A	G52R	0.898
11:60061314:G:C	G52R	0.898
11:60064287:T:A	V107D	0.894

dbSNP variants (sampled 300 via entrez): RS1000264409 (11:60056191 A>G), RS1000719154 (11:60056538 T>A,C,G), RS1000851278 (11:60064550 GTCT>G), RS1000919329 (11:60057954 A>G), RS1000942018 (11:60066539 T>C), RS1001000586 (11:60054997 A>T), RS1001044207 (11:60060681 G>A), RS1001644949 (11:60061747 A>C), RS1001754990 (11:60055869 A>G,T), RS1001923287 (11:60060348 T>C), RS1002101285 (11:60055732 C>T), RS1002431904 (11:60070063 A>G,T), RS1002577022 (11:60070840 T>A,C), RS1002620854 (11:60071235 C>A,T), RS1002856067 (11:60067553 T>C)

Disease associations

OMIM: gene MIM:606498 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001424_4	Vitamin B12 levels	3.000000e-15
GCST002422_4	Alzheimer’s disease	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004620	vitamin B12 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
fluorene-9-bisphenol	decreases expression	1
alpha phellandrene	decreases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	increases expression	1
Decitabine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cyclophosphamide	decreases expression	1
Hydrogen Peroxide	decreases expression	1
Phthalic Acids	increases methylation	1
T-2 Toxin	decreases expression	1
Butyric Acid	increases expression	1

Clinical trials (associated diseases)

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