MS4A4A

Summary

MS4A4A (membrane spanning 4-domains A4A, HGNC:13371) is a protein-coding gene on chromosome 11q12.2, encoding Membrane-spanning 4-domains subfamily A member 4A (Q96JQ5). May be involved in signal transduction as a component of a multimeric receptor complex.

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features, similar intron/exon splice boundaries, and display unique expression patterns in hematopoietic cells and nonlymphoid tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 51338 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_148975

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13371
Approved symbol	MS4A4A
Name	membrane spanning 4-domains A4A
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	CD20L1, MS4A7
Ensembl gene	ENSG00000110079
Ensembl biotype	protein_coding
OMIM	606547
Entrez	51338

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 5 nonsense_mediated_decay, 1 retained_intron

ENST00000337908, ENST00000343968, ENST00000527056, ENST00000529950, ENST00000529991, ENST00000532114, ENST00000649552, ENST00000679385, ENST00000679553, ENST00000679988, ENST00000680301, ENST00000680537, ENST00000680560, ENST00000680757, ENST00000680935, ENST00000681157, ENST00000681288, ENST00000681406, ENST00000895188, ENST00000970116, ENST00000970117

RefSeq mRNA: 3 — MANE Select: NM_148975 NM_001243266, NM_024021, NM_148975

CCDS: CCDS58135, CCDS7982

Canonical transcript exons

ENST00000337908 — 7 exons

Exon	Start	End
ENSE00002186525	60308107	60308970
ENSE00003588989	60306100	60306201
ENSE00003600088	60292225	60292384
ENSE00003631865	60301001	60301057
ENSE00003639476	60297197	60297325
ENSE00003671813	60302559	60302717
ENSE00003850038	60280666	60280716

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 95.57.

FANTOM5 (CAGE): breadth broad, TPM avg 8.4578 / max 1499.8503, expressed in 412 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114451	5.8034	385
114447	0.9914	194
114448	0.5561	155
114450	0.5256	154
114449	0.3979	149
114452	0.1833	96

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	95.57	gold quality
placenta	UBERON:0001987	94.76	gold quality
decidua	UBERON:0002450	94.49	gold quality
right coronary artery	UBERON:0001625	94.16	gold quality
synovial joint	UBERON:0002217	92.68	gold quality
spleen	UBERON:0002106	92.55	gold quality
lower lobe of lung	UBERON:0008949	92.40	gold quality
omental fat pad	UBERON:0010414	92.35	gold quality
peritoneum	UBERON:0002358	92.27	gold quality
layer of synovial tissue	UBERON:0007616	91.82	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.78	gold quality
monocyte	CL:0000576	91.69	gold quality
right lung	UBERON:0002167	91.67	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.61	gold quality
mononuclear cell	CL:0000842	91.13	gold quality
rectum	UBERON:0001052	90.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.88	gold quality
mucosa of stomach	UBERON:0001199	90.79	gold quality
heart right ventricle	UBERON:0002080	90.71	gold quality
upper lobe of left lung	UBERON:0008952	90.68	gold quality
upper lobe of lung	UBERON:0008948	90.51	gold quality
leukocyte	CL:0000738	90.50	gold quality
right adrenal gland cortex	UBERON:0035827	90.47	gold quality
vermiform appendix	UBERON:0001154	90.46	gold quality
lymph node	UBERON:0000029	90.44	gold quality
adipose tissue	UBERON:0001013	89.87	gold quality
descending thoracic aorta	UBERON:0002345	89.69	gold quality
right adrenal gland	UBERON:0001233	89.61	gold quality
superficial temporal artery	UBERON:0001614	89.51	gold quality
left adrenal gland	UBERON:0001234	89.14	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	84.64
E-MTAB-6701	yes	68.83
E-CURD-122	yes	66.61
E-GEOD-135922	yes	57.79
E-HCAD-10	yes	55.58
E-MTAB-8410	yes	44.74
E-MTAB-6678	yes	42.87
E-ANND-3	yes	34.20
E-MTAB-10553	yes	26.00
E-MTAB-10287	yes	23.11
E-HCAD-9	yes	19.55
E-CURD-112	yes	18.51
E-MTAB-10042	yes	10.15
E-MTAB-5061	no	3.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting MS4A4A, 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-1252-5P	100.00	69.80	2774
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577

Literature-anchored findings (GeneRIF, showing 7)

• Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. (PMID:21460841)
• Single nucleotide polymorphisms in APOE-epsilon4, CLU and MS4A4A influence both Alzheimer disease risk and cerebrospinal fluid Amyloid-beta1-42 levels. (PMID:23573206)
• MS4A4 in human mast cells effects ligand-induced KIT endocytosis pathways and reduced receptor recycling to the cell surface, thus promoting KIT signaling in the endosomes while reducing that in the plasma membrane. (PMID:25717186)
• MS4A4A expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. (PMID:28303902)
• MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of natural killer cell-mediated resistance to metastasis. (PMID:31263276)
• The FcepsilonRIbeta homologue, MS4A4A, promotes FcepsilonRI signal transduction and store-operated Ca(2+) entry in human mast cells. (PMID:32240745)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ms4a4a	ENSMUSG00000101389
rattus_norvegicus	Ms4a4a	ENSRNOG00000050024

Paralogs (16): MS4A12 (ENSG00000071203), MS4A6A (ENSG00000110077), MS4A3 (ENSG00000149516), 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 4A — Q96JQ5 (reviewed: Q96JQ5)

Alternative names: CD20 antigen-like 1, Four-span transmembrane protein 1

All UniProt accessions (11): Q96JQ5, A0A384MDW1, A0A3B3ITV6, A0A7P0T8A0, A0A7P0T9I4, A0A7P0TA01, A0A7P0TAE4, A0A7P0Z422, A0A7P0Z4L9, F8W866, H0YE49

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in signal transduction as a component of a multimeric receptor complex.

Subcellular location. Membrane.

Tissue specificity. Variable expression in multiple hemopoietic cell lines.

Similarity. Belongs to the MS4A family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96JQ5-1	1	yes
Q96JQ5-2	2

RefSeq proteins (3): NP_001230195, NP_076926, NP_683876* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007237	CD20-like_TM	Domain
IPR030417	MS4A	Family

Pfam: PF04103

UniProt features (17 total): topological domain 5, transmembrane region 4, sequence variant 3, sequence conflict 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96JQ5-F1	73.38	0.38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 250 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, WALLACE_PROSTATE_CANCER_RACE_UP, MCLACHLAN_DENTAL_CARIES_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, EVI1_05, GOCC_TRANS_GOLGI_NETWORK, OCT1_03, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, VANHARANTA_UTERINE_FIBROID_DN, HAHTOLA_CTCL_PATHOGENESIS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, HAHTOLA_SEZARY_SYNDROM_UP, VANTVEER_BREAST_CANCER_POOR_PROGNOSIS, ACEVEDO_LIVER_CANCER_UP

GO Biological Process (0):

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

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), plasma membrane raft (GO:0044853), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
binding	1
membrane	1
cell periphery	1
plasma membrane	1
membrane raft	1
plasma membrane region	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1066 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MS4A4A	MS4A6E	Q96DS6	976
MS4A4A	MS4A10	Q96PG2	832
MS4A4A	VSIG4	Q9Y279	823
MS4A4A	ABCA7	Q8IZY2	713
MS4A4A	CD2AP	Q9Y5K6	697
MS4A4A	PICALM	Q13492	677
MS4A4A	BIN1	O00499	625
MS4A4A	CD163	Q86VB7	624
MS4A4A	EPHA1	P21709	623
MS4A4A	SORL1	Q92673	620
MS4A4A	CLU	P10909	597
MS4A4A	CD33	P20138	583
MS4A4A	ZCWPW1	Q9H0M4	581
MS4A4A	IRF5	Q13568	580
MS4A4A	CCR8	P51685	571

IntAct

50 interactions, top by confidence:

A	B	Type	Score
MS4A4A	RPRM	psi-mi:“MI:0915”(physical association)	0.600
CMTM7	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
TMUB2	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
NRG1	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
CLDN19	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
MAL	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
PLP1	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
MS4A4A	LPAR3	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
UPK1B	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
RUSF1	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0E1	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
SERTM1	MS4A4A	psi-mi:“MI:0915”(physical association)	0.560
MS4A4A	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
CSE1L	MS4A4A	psi-mi:“MI:0915”(physical association)	0.500
MS4A4A	MON2	psi-mi:“MI:0914”(association)	0.350
CMTM7	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
TMUB2	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
MS4A4A	NRG1	psi-mi:“MI:0915”(physical association)	0.000
CLDN19	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
RPRM	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
SEC22A	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
MAL	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
PLP1	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000
LPAR3	MS4A4A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (42): ACADSB (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), AGPAT2 (Affinity Capture-MS), ALDH3A2 (Affinity Capture-MS), ATP6V1H (Affinity Capture-MS), CAND1 (Affinity Capture-MS), CHP1 (Affinity Capture-MS), CSE1L (Affinity Capture-MS), DNAAF5 (Affinity Capture-MS), KIAA0368 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), FLOT2 (Affinity Capture-MS), HIGD1A (Affinity Capture-MS), HSD17B12 (Affinity Capture-MS), ILVBL (Affinity Capture-MS)

ESM2 similar proteins: A0A0A7EPL0, A2RV66, A4QP16, A6QPF4, C4QM85, F4JYG0, O35892, P11836, P13386, P19437, P20490, P41739, P53762, P56645, P70326, P79778, Q01362, Q148B6, Q29131, Q3C1V0, Q3C2E2, Q3SA47, Q3UNB8, Q3V3Q4, Q3YBM2, Q5I2P1, Q5JT82, Q5R8D6, Q5R8E0, Q60HE7, Q68FU0, Q6A058, Q8BVM2, Q8N1N2, Q8NDZ0, Q8QGQ8, Q8WUU8, Q920C4, Q92540, Q96HJ5

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3425 predictions. Top by Δscore:

Variant	Effect	Δscore
11:60229907:CTTA:C	donor_loss	1.0000
11:60229908:TTACC:T	donor_loss	1.0000
11:60229909:TACCC:T	donor_loss	1.0000
11:60229910:AC:A	donor_gain	1.0000
11:60229910:ACC:A	donor_gain	1.0000
11:60229911:C:CT	donor_loss	1.0000
11:60229911:CC:C	donor_gain	1.0000
11:60229911:CCC:C	donor_gain	1.0000
11:60280715:AGGT:A	donor_loss	1.0000
11:60280717:G:GA	donor_loss	1.0000
11:60290195:G:T	donor_gain	1.0000
11:60292223:A:AG	acceptor_gain	1.0000
11:60292224:G:GG	acceptor_gain	1.0000
11:60300999:A:AG	acceptor_gain	1.0000
11:60301000:G:GA	acceptor_gain	1.0000
11:60301000:GTTT:G	acceptor_gain	1.0000
11:60301000:GTTTA:G	acceptor_gain	1.0000
11:60301053:GCCTG:G	donor_gain	1.0000
11:60301058:G:GG	donor_gain	1.0000
11:60301059:T:TC	donor_loss	1.0000
11:60214615:C:CC	acceptor_gain	0.9900
11:60228510:T:TC	acceptor_gain	0.9900
11:60228730:C:G	acceptor_gain	0.9900
11:60229906:ACTT:A	donor_loss	0.9900
11:60229910:A:AC	donor_gain	0.9900
11:60229910:ACCC:A	donor_gain	0.9900
11:60229911:C:CC	donor_gain	0.9900
11:60229911:CCCC:C	donor_gain	0.9900
11:60229911:CCCCA:C	donor_gain	0.9900
11:60280712:GAAAG:G	donor_gain	0.9900

AlphaMissense

1555 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:60302589:A:C	S140R	0.992
11:60302591:C:A	S140R	0.992
11:60302591:C:G	S140R	0.992
11:60301001:T:C	F111L	0.986
11:60301003:T:A	F111L	0.986
11:60301003:T:G	F111L	0.986
11:60292355:T:C	F58L	0.984
11:60292357:C:A	F58L	0.984
11:60292357:C:G	F58L	0.984
11:60302582:T:A	N137K	0.978
11:60302582:T:G	N137K	0.978
11:60302568:A:C	S133R	0.973
11:60302570:T:A	S133R	0.973
11:60302570:T:G	S133R	0.973
11:60301014:G:A	G115E	0.970
11:60297311:T:A	W106R	0.969
11:60297311:T:C	W106R	0.969
11:60297230:A:C	S79R	0.967
11:60297232:C:A	S79R	0.967
11:60297232:C:G	S79R	0.967
11:60292356:T:G	F58C	0.965
11:60302631:A:C	S154R	0.965
11:60302633:C:A	S154R	0.965
11:60302633:C:G	S154R	0.965
11:60292382:G:T	G67W	0.963
11:60306127:A:C	S192R	0.962
11:60306129:T:A	S192R	0.962
11:60306129:T:G	S192R	0.962
11:60302602:C:A	A144D	0.961
11:60301031:G:C	A121P	0.960

dbSNP variants (sampled 300 via entrez): RS1000071211 (11:60303448 C>T), RS1000123367 (11:60303232 T>G), RS1000137497 (11:60280845 G>A,T), RS1000180184 (11:60279557 T>C), RS1000639620 (11:60287545 C>T), RS1000766053 (11:60285606 G>C), RS1000829655 (11:60281105 A>G,T), RS1000951239 (11:60305614 A>C), RS1000978005 (11:60295435 A>T), RS1001003542 (11:60305197 G>C,T), RS1001123820 (11:60301701 G>A), RS1001228364 (11:60306658 G>A), RS1001241776 (11:60295731 G>A), RS1001329315 (11:60304521 G>A), RS1001447707 (11:60298556 T>C)

Disease associations

OMIM: gene MIM:606547 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001026_2	Alzheimer’s disease (late onset)	8.000000e-12
GCST002817_25	Alzheimer’s disease in APOE e4- carriers	2.000000e-09
GCST004121_10	Fibrinogen levels	3.000000e-09
GCST007614_23	C-reactive protein levels	2.000000e-09
GCST008706_1	Cerebrospinal fluid sTREM-2 levels	5.000000e-21
GCST008706_2	Cerebrospinal fluid sTREM-2 levels	2.000000e-11
GCST011369_20	Iron status biomarkers (ferritin levels)	3.000000e-09
GCST90002393_230	Monocyte count	8.000000e-24
GCST90002394_468	Monocyte percentage of white cells	8.000000e-16

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0010151	soluble triggering receptor expressed on myeloid cells 2 measurement
EFO:0004459	ferritin measurement
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	2
Nickel	increases expression	2
sodium arsenite	affects methylation	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
mesotrione	affects methylation, increases abundance	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Acetaminophen	decreases expression	1
Calcitriol	decreases expression	1
Catechin	affects cotreatment, decreases expression	1
Herbicides	affects methylation, increases abundance	1
Phthalic Acids	increases methylation	1
Smoke	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_VD90	300-19 GFP-MS4A4A	Cancer cell line
CVCL_VD93	BJAB GFP-MS4A4A	Cancer cell line	Female
CVCL_VE00	BJAB HA-MS4A4A	Cancer cell line	Female

Clinical trials (associated diseases)

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