TAFA4

Summary

TAFA4 (TAFA chemokine like family member 4, HGNC:21591) is a protein-coding gene on chromosome 3p14.1, encoding Chemokine-like protein TAFA-4 (Q96LR4). Modulates injury-induced and chemical pain hypersensitivity.

This gene is a member of the TAFA family which is composed of five highly homologous genes that encode small secreted proteins. These proteins contain conserved cysteine residues at fixed positions, and are distantly related to MIP-1alpha, a member of the CC-chemokine family. The TAFA proteins are predominantly expressed in specific regions of the brain, and are postulated to function as brain-specific chemokines or neurokines, that act as regulators of immune and nervous cells. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 151647 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_182522

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21591
Approved symbol	TAFA4
Name	TAFA chemokine like family member 4
Location	3p14.1
Locus type	gene with protein product
Status	Approved
Aliases	TAFA-4
Ensembl gene	ENSG00000163377
Ensembl biotype	protein_coding
OMIM	617498
Entrez	151647

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000295569, ENST00000495737, ENST00000634242, ENST00000917807

RefSeq mRNA: 2 — MANE Select: NM_182522 NM_001005527, NM_182522

CCDS: CCDS2907

Canonical transcript exons

ENST00000295569 — 6 exons

Exon	Start	End
ENSE00001073941	68880730	68880845
ENSE00001073943	68739075	68739199
ENSE00001073945	68752863	68753018
ENSE00001359530	68885175	68885310
ENSE00001359533	68932240	68932547
ENSE00001365595	68731766	68733153

Expression profiles

Bgee: expression breadth broad, 96 present calls, max score 89.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4253 / max 281.3009, expressed in 256 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42944	2.4253	256

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.64	gold quality
oocyte	CL:0000023	87.60	gold quality
secondary oocyte	CL:0000655	86.74	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.46	gold quality
right adrenal gland cortex	UBERON:0035827	79.31	gold quality
decidua	UBERON:0002450	77.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.85	gold quality
right adrenal gland	UBERON:0001233	76.60	gold quality
adrenal cortex	UBERON:0001235	75.18	gold quality
left adrenal gland	UBERON:0001234	74.71	gold quality
left adrenal gland cortex	UBERON:0035825	73.90	gold quality
spinal cord	UBERON:0002240	73.69	gold quality
adrenal gland	UBERON:0002369	73.51	gold quality
prefrontal cortex	UBERON:0000451	68.27	gold quality
adrenal tissue	UBERON:0018303	66.70	gold quality
hypothalamus	UBERON:0001898	66.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.74	gold quality
islet of Langerhans	UBERON:0000006	64.27	gold quality
substantia nigra	UBERON:0002038	62.34	gold quality
gall bladder	UBERON:0002110	61.56	gold quality
anterior cingulate cortex	UBERON:0009835	61.31	gold quality
dorsal plus ventral thalamus	UBERON:0001897	60.81	silver quality
buccal mucosa cell	CL:0002336	60.33	silver quality
frontal cortex	UBERON:0001870	60.28	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.13	gold quality
midbrain	UBERON:0001891	60.10	gold quality
neocortex	UBERON:0001950	59.56	gold quality
right frontal lobe	UBERON:0002810	58.92	gold quality
putamen	UBERON:0001874	58.58	gold quality
corpus callosum	UBERON:0002336	58.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	21.91
E-ANND-3	yes	4.57
E-MTAB-8060	no	50.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting TAFA4, 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-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3133	99.81	70.92	3506

Literature-anchored findings (GeneRIF, showing 18)

• FAM19A4 is a novel ligand of formyl peptide receptor 1. (PMID:25109685)
• High methylation of FAM19A4 is associated with cervical carcinomas. (PMID:25281488)
• among high risk HPV-positive women from an outpatient population aged >/= 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with high-grade cervical intraepithelial neoplasia and cervical cancer (PMID:26317579)
• FAM19A4/mir124-2 methylation analysis performs equally well in HPV-positive lavage- and brush self-samples to identify women with CIN3+. In combination with HPV16/18 genotyping, significantly higher CIN3+ sensitivities are obtained, at decreased specificity. (PMID:26921784)
• With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples (PMID:27415009)
• Hypermethylation of FAM19A4/miR124-2 in the self-sample was tested in a quantitative methylation specific PCR and compared between lesions caused by HPV16/18 and other hrHPV genotypes. There were no differences in the percentages of positive FAM19A4/miR124-2 methylation assays between lesions caused by HPV16/18 (73.8% in CIN3+) or other hrHPV genotypes (66.7% in CIN3+) (p=0.538). (PMID:30219239)
• FAM19A4 methylation analysis may serve as an auxiliary screening method for diagnosis of cervical (pre)cancer. (PMID:30486875)
• Among HPV positive women aged >/=30 years, a negative FAM19A4/miR124-2 methylation test provides a similar safety in terms of long-term CIN3+ risk compared with a negative cytology test, while the CIN3+risk following a positive methylation test justifies immediate colposcopy referral. (PMID:31182225)
• detection of FAM19A4 promoter methylation in cervical exfoliated cells has a high clinical value of discriminating >/=HSIL lesions (PMID:31269601)
• The use of molecular markers for cervical screening of women living with HIV in South Africa. (PMID:31385866)
• FAM19A4/miR124-2 methylation in invasive cervical cancer: A retrospective cross-sectional worldwide study. (PMID:31390052)
• Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124-2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions. (PMID:32022461)
• Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study. (PMID:32997803)
• Risk-stratification of HPV-positive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping. (PMID:34743198)
• Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study). (PMID:35512257)
• FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years. (PMID:35686306)
• Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Orebro, Sweden. (PMID:36137165)
• Signals from the TAFA4-PTEN-PU.1 axis alleviate nasal allergy by modulating the expression of FcepsilonRI in mast cells. (PMID:36368013)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tafa4a	ENSDARG00000077626
mus_musculus	Tafa4	ENSMUSG00000046500
rattus_norvegicus	Tafa4	ENSRNOG00000005830

Paralogs (3): TAFA1 (ENSG00000183662), TAFA3 (ENSG00000184599), TAFA2 (ENSG00000198673)

Protein

Protein identifiers

Chemokine-like protein TAFA-4 — Q96LR4 (reviewed: Q96LR4)

All UniProt accessions (3): A0A0U1RQN7, C9JUW7, Q96LR4

UniProt curated annotations — full annotation on UniProt →

Function. Modulates injury-induced and chemical pain hypersensitivity. Ligand of FPR1, can chemoattract macrophages, promote phagocytosis and increase ROS release.

Subcellular location. Secreted.

Tissue specificity. Expressed in brain. Expressed in LPS-stimulated monocytes and macrophages, especially in polarized M1.

Similarity. Belongs to the TAFA family.

RefSeq proteins (2): NP_001005527, NP_872328* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR020350	Chemokine-like_TAFA	Family
IPR051743	TAFA_chemokine-like	Family

Pfam: PF12020

UniProt features (2 total): signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LR4-F1	85.57	0.60

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 95 (showing top): RNGTGGGC_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, GOBP_SENSORY_PERCEPTION_OF_PAIN, MYCMAX_01, GOBP_REGULATION_OF_SENSORY_PERCEPTION, TGANTCA_AP1_C, GOBP_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_REGULATION_OF_SYSTEM_PROCESS

GO Biological Process (7): phagocytosis (GO:0006909), regulation of signaling receptor activity (GO:0010469), regulation of membrane potential (GO:0042391), superoxide anion generation (GO:0042554), macrophage chemotaxis (GO:0048246), regulation of sensory perception of pain (GO:0051930), signal transduction (GO:0007165)

GO Molecular Function (2): receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), synaptic vesicle membrane (GO:0030672), glutamatergic synapse (GO:0098978), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endocytosis	1
regulation of signal transduction	1
signaling receptor activity	1
regulation of molecular function	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
superoxide metabolic process	1
leukocyte chemotaxis	1
macrophage migration	1
sensory perception of pain	1
regulation of sensory perception	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
binding	1
synaptic vesicle	1
exocytic vesicle membrane	1
synapse	1
cellular anatomical structure	1

Protein interactions and networks

STRING

520 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TAFA4	PHACTR3	Q96KR7	730
TAFA4	RUBCNL	Q9H714	582
TAFA4	EPB41L3	Q9Y2J2	582
TAFA4	ZNF582	Q96NG8	579
TAFA4	FPR1	P21462	564
TAFA4	SLC17A8	Q8NDX2	562
TAFA4	PRDM14	Q9GZV8	511
TAFA4	MRGPRD	Q8TDS7	488
TAFA4	PAX1	P15863	480
TAFA4	ZNF671	Q8TAW3	479
TAFA4	CADM1	Q9BY67	446
TAFA4	HS3ST2	Q9Y278	431
TAFA4	INPP1	P49441	431
TAFA4	RXFP3	Q9NSD7	419
TAFA4	SOX1	O00570	399
TAFA4	JAM3	Q9BX67	399

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TAFA4	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
APPBP2	TAFA4	psi-mi:“MI:0915”(physical association)	0.560
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (93): FAM19A4 (Two-hybrid), NRXN3 (Affinity Capture-MS), SEZ6L2 (Affinity Capture-MS), AVL9 (Affinity Capture-MS), VCAN (Affinity Capture-MS), LRRC4B (Affinity Capture-MS), PLXNA2 (Affinity Capture-MS), SUSD5 (Affinity Capture-MS), MRC2 (Affinity Capture-MS), TM7SF3 (Affinity Capture-MS), LIFR (Affinity Capture-MS), LEPR (Affinity Capture-MS), ITGA5 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), ITPR2 (Affinity Capture-MS)

ESM2 similar proteins: A0A291NVT7, A0A4Y5X186, A0A4Y5X1A7, B0VXV3, B0VXV4, O42493, O43278, P01060, P05486, P08163, P0DN42, P0DN43, P0DTJ2, P0DTJ3, P16229, P17668, P48250, P56688, P58990, P67862, Q00945, Q07662, Q07663, Q08E66, Q23247, Q2XXR7, Q2XXR8, Q330K6, Q4R128, Q56R10, Q56R11, Q58T08, Q7M428, Q7TPG5, Q7TPG6, Q7TPG7, Q7TPG8, Q7TQN3, Q7Z5A8, Q7Z5A9

Diamond homologs: M0R7X9, Q3ZBS2, Q5R6N2, Q7TPG5, Q7TPG6, Q7TPG7, Q7TPG8, Q7Z5A7, Q7Z5A8, Q7Z5A9, Q8N3H0, Q91WE9, Q96LR4, Q9N0D3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2863 predictions. Top by Δscore:

Variant	Effect	Δscore
3:68752857:TCTTA:T	donor_loss	1.0000
3:68752858:CTTAC:C	donor_loss	1.0000
3:68752859:TTACC:T	donor_loss	1.0000
3:68752860:TA:T	donor_loss	1.0000
3:68752862:CCT:C	donor_loss	1.0000
3:68885216:ATT:A	donor_gain	1.0000
3:68885326:C:CT	acceptor_gain	1.0000
3:68923334:T:TA	donor_gain	1.0000
3:68932238:A:AC	donor_gain	1.0000
3:68932239:C:CC	donor_gain	1.0000
3:68932239:CT:C	donor_gain	1.0000
3:68932239:CTCGA:C	donor_gain	1.0000
3:68752926:TG:T	donor_gain	0.9900
3:68753019:CTA:C	acceptor_loss	0.9900
3:68753020:T:C	acceptor_loss	0.9900
3:68753023:T:C	acceptor_gain	0.9900
3:68753023:T:TC	acceptor_gain	0.9900
3:68753026:G:GC	acceptor_gain	0.9900
3:68753029:A:AC	acceptor_gain	0.9900
3:68753029:A:C	acceptor_gain	0.9900
3:68823202:T:C	acceptor_gain	0.9900
3:68881702:C:CT	acceptor_gain	0.9900
3:68885168:ATCTT:A	donor_loss	0.9900
3:68885169:TCTTA:T	donor_loss	0.9900
3:68885170:CTTA:C	donor_loss	0.9900
3:68885171:TTA:T	donor_loss	0.9900
3:68885172:TACCT:T	donor_loss	0.9900
3:68885173:A:AT	donor_loss	0.9900
3:68885174:C:A	donor_loss	0.9900
3:68885177:TGGGG:T	donor_gain	0.9900

AlphaMissense

908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:68739111:C:A	W125C	1.000
3:68739111:C:G	W125C	1.000
3:68739174:C:A	W104C	1.000
3:68739174:C:G	W104C	1.000
3:68739105:A:C	C127W	0.999
3:68739106:C:T	C127Y	0.999
3:68739113:A:G	W125R	0.999
3:68739113:A:T	W125R	0.999
3:68739139:C:G	C116S	0.999
3:68739140:A:T	C116S	0.999
3:68739172:C:G	C105S	0.999
3:68739173:A:T	C105S	0.999
3:68739176:A:G	W104R	0.999
3:68739176:A:T	W104R	0.999
3:68752871:C:G	C93S	0.999
3:68752871:C:T	C93Y	0.999
3:68752872:A:T	C93S	0.999
3:68752895:C:T	G85D	0.999
3:68752915:G:C	C78W	0.999
3:68752916:C:T	C78Y	0.999
3:68752921:G:C	C76W	0.999
3:68752922:C:G	C76S	0.999
3:68752923:A:G	C76R	0.999
3:68752923:A:T	C76S	0.999
3:68752928:A:T	V74D	0.999
3:68752991:C:G	C53S	0.999
3:68752992:A:T	C53S	0.999
3:68739084:T:A	K134N	0.998
3:68739084:T:G	K134N	0.998
3:68739106:C:G	C127S	0.998

dbSNP variants (sampled 300 via entrez): RS1000006418 (3:68761396 C>A,G,T), RS1000043438 (3:68900217 G>A), RS1000051329 (3:68789833 A>G), RS1000053790 (3:68831802 A>C), RS1000067759 (3:68931446 T>G), RS1000071548 (3:68875351 A>T), RS1000089089 (3:68756447 G>T), RS1000096878 (3:68855779 C>A,G,T), RS1000134697 (3:68899464 A>G), RS1000140261 (3:68807741 C>G), RS1000156585 (3:68831430 T>A), RS1000170574 (3:68867827 C>A), RS1000174822 (3:68733604 G>A,C), RS1000206786 (3:68911223 T>A,G), RS1000216161 (3:68919675 C>T)

Disease associations

OMIM: gene MIM:617498 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004033_4	QRS interval (sulfonylurea treatment interaction)	1.000000e-06
GCST009391_1553	Metabolite levels	3.000000e-06
GCST009516_5	Non-del(5q) myelodysplastic syndromes	4.000000e-06
GCST009524_110	Household income (MTAG)	3.000000e-08
GCST010002_429	Refractive error	7.000000e-24
GCST010059_4	Physiological traits	1.000000e-06
GCST010059_9	Physiological traits	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007922	response to sulfonylurea
EFO:0009776	ornithine measurement
EFO:0009695	household income

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
entinostat	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Ethanol	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Quercetin	decreases expression	1
Dihydrotestosterone	increases expression	1
Triclosan	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases expression	1

Clinical trials (associated diseases)

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