COXFA4L3

Summary

COXFA4L3 (cytochrome c oxidase associated subunit FA4L3, HGNC:29898) is a protein-coding gene on chromosome 15q21.1, encoding Cytochrome c oxidase associated subunit FA4L3 (Q9C002). Mitochondrial small peptide that orchestrates a two-pronged immunoregulatory mechanism in response to inflammatory stimuli.

This gene was first identified in a study of human esophageal squamous cell carcinoma tissues. Levels of both the message and protein are reduced in carcinoma samples. In adult human tissues, this gene is expressed in the the esophagus, stomach, small intestine, colon and placenta. Alternatively spliced transcript variants that encode the same protein have been identified.

Source: NCBI Gene 84419 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 7 total
• MANE Select transcript: NM_197955

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29898
Approved symbol	COXFA4L3
Name	cytochrome c oxidase associated subunit FA4L3
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	NMES1, MIR147BHG, COXFA4L3, MOCCI, MISTRAV
Ensembl gene	ENSG00000166920
Ensembl biotype	protein_coding
OMIM	608409
Entrez	84419

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000344300, ENST00000396650, ENST00000558632, ENST00000850626, ENST00000960373

RefSeq mRNA: 2 — MANE Select: NM_197955 NM_032413, NM_197955

CCDS: CCDS10124

Canonical transcript exons

ENST00000396650 — 5 exons

Exon	Start	End
ENSE00001107776	45432948	45433340
ENSE00004282371	45432072	45432132
ENSE00004282372	45431001	45431086
ENSE00004282374	45430770	45430832
ENSE00004282375	45430610	45430655

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 99.83.

FANTOM5 (CAGE): breadth broad, TPM avg 57.7143 / max 2645.0921, expressed in 807 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146435	57.7143	807

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.83	gold quality
rectum	UBERON:0001052	99.74	gold quality
right testis	UBERON:0004534	98.04	gold quality
lower esophagus mucosa	UBERON:0035834	97.93	gold quality
left testis	UBERON:0004533	97.88	gold quality
vermiform appendix	UBERON:0001154	97.59	gold quality
testis	UBERON:0000473	97.42	gold quality
islet of Langerhans	UBERON:0000006	97.35	gold quality
duodenum	UBERON:0002114	95.41	gold quality
esophagus mucosa	UBERON:0002469	95.28	gold quality
skin of abdomen	UBERON:0001416	95.18	gold quality
placenta	UBERON:0001987	94.07	gold quality
transverse colon	UBERON:0001157	94.02	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.48	gold quality
zone of skin	UBERON:0000014	92.77	gold quality
small intestine	UBERON:0002108	92.22	gold quality
skin of leg	UBERON:0001511	91.06	gold quality
gall bladder	UBERON:0002110	89.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.73	gold quality
intestine	UBERON:0000160	86.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.81	gold quality
pancreas	UBERON:0001264	84.34	gold quality
colon	UBERON:0001155	84.19	gold quality
colonic epithelium	UBERON:0000397	83.49	gold quality
body of stomach	UBERON:0001161	83.02	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.33	gold quality
vagina	UBERON:0000996	81.66	gold quality
smooth muscle tissue	UBERON:0001135	81.56	gold quality
mucosa of stomach	UBERON:0001199	81.53	gold quality
endometrium	UBERON:0001295	81.30	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	9320.61
E-GEOD-139324	yes	4642.23
E-MTAB-8322	yes	2953.62
E-CURD-88	yes	2520.94
E-MTAB-6653	yes	2312.93
E-MTAB-8410	yes	2232.06
E-HCAD-13	yes	1394.91
E-MTAB-10287	yes	1218.80
E-GEOD-86618	yes	843.54
E-CURD-114	yes	47.40
E-CURD-46	yes	33.93
E-HCAD-31	yes	22.22
E-MTAB-5061	yes	18.46
E-MTAB-7381	no	1068.27
E-GEOD-125970	no	42.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting COXFA4L3, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-198	98.70	67.32	920
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-3144-3P	98.15	67.34	677

Literature-anchored findings (GeneRIF, showing 2)

• The negative correlation of NMES1 expression with esophageal oncogenesis suggests its suppressive role in tumorigenesis of the esophagus, while the precise function of NMES1 still needs further investigation. (PMID:12209954)
• Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity. (PMID:33837217)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	C18H15orf48	ENSDARG00000092903
mus_musculus	AA467197	ENSMUSG00000033213
rattus_norvegicus	C3h15orf48	ENSRNOG00000067060

Paralogs (2): NDUFA4L2 (ENSG00000185633), NDUFA4 (ENSG00000189043)

Protein

Protein identifiers

Cytochrome c oxidase associated subunit FA4L3 — Q9C002 (reviewed: Q9C002)

Alternative names: Modulator of cytochrome C oxidase during inflammation protein, Normal mucosa of esophagus-specific gene 1 protein, Protein FOAP-11

All UniProt accessions (1): Q9C002

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial small peptide that orchestrates a two-pronged immunoregulatory mechanism in response to inflammatory stimuli. Replaces the canonical cytochrome c oxidase subunit COXFA4 in mitochondrial complex IV and targets it to degradation, attenuating mitochondrial respiration, reducing membrane potential as well as ROS generation and modulates innate immune signaling. Additionally, initiates stress-independent autophagy by lowering ATP levels, activating AMPK-ULK1 signaling, boosting glutathione production, and thereby mitigating oxidative stress and supporting immune tolerance.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed mainly in stomach, placenta, small intestine and colon, as well as in normal mucosa of esophagus. Down-regulated in esophageal squamous cell carcinoma. Expressed in macrophages.

Induction. Induced by LPS and inflammatory cytokines such as TNF and IL1A.

Miscellaneous. The same gene encodes for protein COXFA4L3 and miRNA miR-147. Both are expressed in simultaneously and work together to target COXFA4 for degradation and to regulate inflammation and immunity.

Similarity. Belongs to the complex IV COXFA4 subunit family.

RefSeq proteins (2): NP_115789, NP_922946* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010530	B12D	Family

Pfam: PF06522

UniProt features (2 total): chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C002-F1	89.97	0.49

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 169 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, IVANOVA_HEMATOPOIESIS_MATURE_CELL, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP, CORRE_MULTIPLE_MYELOMA_UP, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_16D_UP, IZADPANAH_STEM_CELL_ADIPOSE_VS_BONE_UP, RIGGI_EWING_SARCOMA_PROGENITOR_UP, GOCC_CYTOCHROME_COMPLEX, ZHENG_BOUND_BY_FOXP3, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX, HAMAI_APOPTOSIS_VIA_TRAIL_UP, DODD_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (1): response to bacterium (GO:0009617)

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

GO Cellular Component (3): nucleus (GO:0005634), mitochondrion (GO:0005739), respiratory chain complex IV (GO:0045277)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
response to other organism	1
binding	1
cytoplasm	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1

Protein interactions and networks

STRING

830 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COXFA4L3	COXFA4	O00483	965
COXFA4L3	RTKN	Q9BST9	413
COXFA4L3	TASL	Q9HAI6	407
COXFA4L3	RBM38	Q9H0Z9	405
COXFA4L3	SUOX	P51687	395
COXFA4L3	C11orf87	Q6NUJ2	362
COXFA4L3	EPB41L3	Q9Y2J2	312
COXFA4L3	KRTAP10-7	P60409	311
COXFA4L3	C19orf33	Q9GZP8	310
COXFA4L3	MT1G	P13640	310
COXFA4L3	CLEC18C	Q8NCF0	310
COXFA4L3	FAM161B	Q96MY7	310
COXFA4L3	TFPI2	P48307	305
COXFA4L3	SPRR3	Q9UBC9	305
COXFA4L3	OR2F1	Q13607	305

IntAct

13 interactions, top by confidence:

A	B	Type	Score
HTT	NMES1	psi-mi:“MI:0915”(physical association)	0.560
NMES1	ABL2	psi-mi:“MI:0915”(physical association)	0.370
NMES1	TSSK3	psi-mi:“MI:0915”(physical association)	0.370
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NMES1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
NMES1	TIMM44	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
SLC39A11	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (137): APOOL (Affinity Capture-MS), TBRG4 (Affinity Capture-MS), UQCC2 (Affinity Capture-MS), COX7C (Affinity Capture-MS), CYB5R3 (Affinity Capture-MS), RAB35 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), COX7A2L (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), CPT2 (Affinity Capture-MS), COX7A2 (Affinity Capture-MS), NDUFAF3 (Affinity Capture-MS), COX6C (Affinity Capture-MS), SAMM50 (Affinity Capture-MS), TIMM44 (Affinity Capture-MS)

ESM2 similar proteins: A1L2P2, A1XQT2, A5PJ82, A8MTT3, D2H617, D4ACP2, E2R5I0, F6USH3, G1QDE8, G1S9B8, O95139, P04038, P09669, P0CB93, P0CB94, P11951, P80977, Q02367, Q0MQ88, Q0MQ89, Q0MQ90, Q0MQE0, Q0MQE1, Q0Q4Z0, Q28EM2, Q28GF4, Q29259, Q3UIU2, Q4I8P5, Q5BKW8, Q5RK28, Q68EV8, Q78RX3, Q7YRJ8, Q7YRJ9, Q7YRK0, Q7YRK1, Q7YRK2, Q7YRK3, Q7YRK7

Diamond homologs: O00483, Q01321, Q0MQ97, Q0MQ98, Q0MQ99, Q3SZ44, Q3YAJ5, Q4FZG9, Q4R542, Q5RK28, Q62425, Q6PBH5, Q810Q5, Q9C002, Q9NRX3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

277 predictions. Top by Δscore:

Variant	Effect	Δscore
15:45430830:G:GT	donor_gain	1.0000
15:45430830:GAA:G	donor_gain	1.0000
15:45430833:G:GG	donor_gain	1.0000
15:45432066:TTTTA:T	acceptor_loss	1.0000
15:45432067:TTTA:T	acceptor_loss	1.0000
15:45432068:TTA:T	acceptor_loss	1.0000
15:45432069:TAGC:T	acceptor_loss	1.0000
15:45432070:A:AG	acceptor_gain	1.0000
15:45432070:AGC:A	acceptor_loss	1.0000
15:45432071:G:GG	acceptor_gain	1.0000
15:45432071:GC:G	acceptor_gain	1.0000
15:45432071:GCCT:G	acceptor_gain	1.0000
15:45432071:GCCTT:G	acceptor_gain	1.0000
15:45432128:AAAAG:A	donor_loss	1.0000
15:45432129:AAAGG:A	donor_loss	1.0000
15:45432130:AAGG:A	donor_loss	1.0000
15:45432131:AGGT:A	donor_loss	1.0000
15:45432132:GGTAT:G	donor_loss	1.0000
15:45432133:GT:G	donor_loss	1.0000
15:45432134:T:G	donor_loss	1.0000
15:45432946:A:AG	acceptor_gain	1.0000
15:45432947:G:GA	acceptor_gain	1.0000
15:45432947:GC:G	acceptor_gain	1.0000
15:45432947:GCT:G	acceptor_gain	1.0000
15:45432947:GCTT:G	acceptor_gain	1.0000
15:45432947:GCTTA:G	acceptor_gain	1.0000
15:45430826:G:GT	donor_gain	0.9900
15:45430828:AGGAA:A	donor_gain	0.9900
15:45430829:GGAA:G	donor_gain	0.9900
15:45430829:GGAAG:G	donor_gain	0.9900

AlphaMissense

543 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:45432102:G:C	W51C	0.968
15:45432102:G:T	W51C	0.968
15:45432971:G:C	W69C	0.964
15:45432971:G:T	W69C	0.964
15:45431056:C:A	A31D	0.951
15:45431074:A:T	K37I	0.943
15:45431044:C:A	A27D	0.936
15:45432100:T:A	W51R	0.935
15:45432100:T:C	W51R	0.935
15:45432969:T:A	W69R	0.922
15:45432969:T:C	W69R	0.922
15:45431032:C:A	A23E	0.919
15:45432132:G:C	K61N	0.913
15:45432132:G:T	K61N	0.913
15:45431035:C:A	A24E	0.901
15:45431034:G:C	A24P	0.894
15:45431002:T:C	L13P	0.889
15:45431043:G:C	A27P	0.883
15:45431040:G:A	G26R	0.875
15:45431040:G:C	G26R	0.875
15:45431041:G:A	G26E	0.865
15:45431014:T:A	V17E	0.860
15:45432131:A:C	K61T	0.854
15:45431017:T:A	V18E	0.852
15:45432970:G:C	W69S	0.849
15:45431052:T:C	F30L	0.845
15:45431054:C:A	F30L	0.845
15:45431054:C:G	F30L	0.845
15:45431075:A:C	K37N	0.839
15:45431075:A:T	K37N	0.839

dbSNP variants (sampled 300 via entrez): RS1000447671 (15:45432608 T>C), RS1000711452 (15:45431311 C>A,T), RS1000778417 (15:45430484 C>G,T), RS1001184663 (15:45430969 C>A,T), RS1002813973 (15:45428638 A>T), RS1002894950 (15:45430190 A>G), RS1002980785 (15:45428841 C>T), RS1003130406 (15:45428957 T>G), RS1004190694 (15:45433720 C>G,T), RS1004624364 (15:45430250 T>C), RS1005286846 (15:45433715 C>A), RS1005606693 (15:45433831 G>A,T), RS1006200314 (15:45432289 T>A,C), RS1006237753 (15:45430657 T>TG), RS1006665430 (15:45429031 T>A)

Disease associations

OMIM: gene MIM:608409 | disease phenotypes: MIM:612718

GenCC curated gene-disease

Mondo (1): AGAT deficiency (MONDO:0012996)

Orphanet (1): L-Arginine:glycine amidinotransferase deficiency (Orphanet:35704)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006463_21	Urinary albumin excretion (no hypertensive medication)	1.000000e-08
GCST012020_481	Serum metabolite levels	4.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004285	albuminuria

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567192	Arginine-Glycine Amidinotransferase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

69 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
sodium arsenite	increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
sotorasib	affects cotreatment, increases expression	1
urushiol	increases expression	1
propionaldehyde	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
nickel chloride	increases expression	1
nickel sulfate	increases expression	1
hydroquinone	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	increases expression	1
brequinar	affects expression	1
chromium hexavalent ion	decreases expression	1
entinostat	increases expression	1
lipopolysaccharide, E coli O55-B5	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1CQ	Ubigene THP-1 C15orf48 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns