CYB561A3

Summary

CYB561A3 (cytochrome b561 family member A3, HGNC:23014) is a protein-coding gene on chromosome 11q12.2, encoding Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (Q8NBI2). Transmembrane reductase that uses ascorbate as an electron donor in the cytoplasm and transfers electrons across membranes to reduce iron cations Fe(3+) into Fe(2+) in the lumen of the late endosome and lysosome.

Predicted to enable transmembrane ascorbate ferrireductase activity. Predicted to be involved in intracellular iron ion homeostasis. Located in nucleolus.

Source: NCBI Gene 220002 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 40 total
• MANE Select transcript: NM_153611

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23014
Approved symbol	CYB561A3
Name	cytochrome b561 family member A3
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	LCYTB
Ensembl gene	ENSG00000162144
Ensembl biotype	protein_coding
OMIM	618757
Entrez	220002

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 33 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000294072, ENST00000426130, ENST00000447532, ENST00000535152, ENST00000535177, ENST00000536452, ENST00000536687, ENST00000536915, ENST00000537364, ENST00000537680, ENST00000538263, ENST00000539128, ENST00000539890, ENST00000540139, ENST00000540317, ENST00000540755, ENST00000542361, ENST00000542411, ENST00000544118, ENST00000545361, ENST00000546151, ENST00000884217, ENST00000884218, ENST00000884219, ENST00000884220, ENST00000884221, ENST00000884222, ENST00000884223, ENST00000884224, ENST00000945361, ENST00000945362, ENST00000945363, ENST00000945364, ENST00000945365, ENST00000945366, ENST00000945367, ENST00000945368, ENST00000945369, ENST00000945370, ENST00000945371, ENST00000945372

RefSeq mRNA: 4 — MANE Select: NM_153611 NM_001161452, NM_001161454, NM_001300763, NM_153611

CCDS: CCDS53639, CCDS73296, CCDS8004

Canonical transcript exons

ENST00000294072 — 7 exons

Exon	Start	End
ENSE00001062995	61357733	61357828
ENSE00001236925	61348805	61350422
ENSE00003487077	61356530	61356728
ENSE00003568881	61350991	61351147
ENSE00003571013	61352985	61353139
ENSE00003632352	61353784	61353992
ENSE00003900737	61361733	61361882

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.2582 / max 2021.3992, expressed in 1818 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119985	25.2022	1788
119989	10.1446	1789
119984	4.5032	1493
119979	1.3896	85
119988	0.9432	546
119983	0.6419	150
119981	0.5572	119
119986	0.3319	155
119982	0.1658	65
119987	0.1598	86

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.04	gold quality
right adrenal gland cortex	UBERON:0035827	99.02	gold quality
adrenal cortex	UBERON:0001235	98.90	gold quality
left adrenal gland cortex	UBERON:0035825	98.90	gold quality
left adrenal gland	UBERON:0001234	98.70	gold quality
adrenal gland	UBERON:0002369	97.87	gold quality
ileal mucosa	UBERON:0000331	97.77	gold quality
upper arm skin	UBERON:0004263	97.05	gold quality
lymph node	UBERON:0000029	96.57	gold quality
nipple	UBERON:0002030	96.29	gold quality
mucosa of transverse colon	UBERON:0004991	95.20	gold quality
granulocyte	CL:0000094	94.97	gold quality
stromal cell of endometrium	CL:0002255	94.81	gold quality
spleen	UBERON:0002106	94.44	gold quality
skin of leg	UBERON:0001511	93.59	gold quality
vermiform appendix	UBERON:0001154	93.24	gold quality
trachea	UBERON:0003126	93.19	gold quality
leukocyte	CL:0000738	93.05	gold quality
monocyte	CL:0000576	92.83	gold quality
gall bladder	UBERON:0002110	92.59	gold quality
right ovary	UBERON:0002118	92.52	gold quality
zone of skin	UBERON:0000014	92.39	gold quality
caecum	UBERON:0001153	92.39	gold quality
transverse colon	UBERON:0001157	92.36	gold quality
skin of abdomen	UBERON:0001416	92.31	gold quality
right uterine tube	UBERON:0001302	92.29	gold quality
left ovary	UBERON:0002119	92.08	gold quality
pancreatic ductal cell	CL:0002079	91.95	silver quality
epithelium of nasopharynx	UBERON:0001951	91.90	gold quality
nasopharynx	UBERON:0001728	91.89	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	48.68
E-CURD-122	yes	23.92
E-MTAB-8142	yes	22.83
E-HCAD-1	yes	14.91
E-MTAB-6701	yes	14.67
E-MTAB-8498	yes	13.89
E-CURD-112	yes	12.24
E-MTAB-9467	yes	12.13
E-ANND-3	yes	6.78
E-MTAB-6678	yes	4.96
E-MTAB-5061	no	3.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting CYB561A3, 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-4673	100.00	66.64	1490
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4733-3P	98.35	65.20	994

Literature-anchored findings (GeneRIF, showing 1)

• CYB561A3 is the key lysosomal iron reductase required for Burkitt B-cell growth and survival. (PMID:34232987)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyb561a3b	ENSDARG00000028257
danio_rerio	cyb561a3a	ENSDARG00000056281
mus_musculus	Cyb561a3	ENSMUSG00000034445
rattus_norvegicus	Cyb561a3	ENSRNOG00000020702
drosophila_melanogaster	CG1275	FBGN0035321

Paralogs (2): CYB561 (ENSG00000008283), CYBRD1 (ENSG00000071967)

Protein

Protein identifiers

Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 — Q8NBI2 (reviewed: Q8NBI2)

Alternative names: Cytochrome b ascorbate-dependent protein 3, Cytochrome b561 family member A3, Lysosomal cytochrome b

All UniProt accessions (12): Q8NBI2, F5GWH8, F5GX87, F5H0P5, F5H121, F5H1Q2, F5H240, F5H466, F5H5L0, F5H5Y9, F5H684, F5H832

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane reductase that uses ascorbate as an electron donor in the cytoplasm and transfers electrons across membranes to reduce iron cations Fe(3+) into Fe(2+) in the lumen of the late endosome and lysosome. Reduced iron can then be extruded from the late endosome and lysosome to the cytoplasm by divalent metal-specific transporters. It is therefore most probably involved in endosomal and lysosomal cellular iron homeostasis.

Subunit / interactions. Homodimer.

Subcellular location. Late endosome membrane. Lysosome membrane.

Post-translational modifications. N-glycosylated.

Cofactor. Binds 2 heme b groups non-covalently.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NBI2-1	1	yes
Q8NBI2-2	2

RefSeq proteins (4): NP_001154924, NP_001154926, NP_001287692, NP_705839* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006593	Cyt_b561/ferric_Rdtase_TM	Domain
IPR043205	CYB561/CYBRD1-like	Family

Pfam: PF03188

Catalyzed reactions (Rhea), 1 shown:

• Fe(3+)(out) + L-ascorbate(in) = monodehydro-L-ascorbate radical(in) + Fe(2+)(out) + H(+) (RHEA:30403)

UniProt features (30 total): binding site 11, topological domain 7, transmembrane region 6, sequence conflict 2, chain 1, domain 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NBI2-F1	92.25	0.84

Functional residue map

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

Ligand- & substrate-binding residues (11): 47 (axial binding residue); 67; 76; 80; 83 (axial binding residue); 112–115; 117 (axial binding residue); 149; 156 (axial binding residue); 177; 224

Glycosylation sites (1): 38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 153 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOCC_VACUOLAR_MEMBRANE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, CAGGTCC_MIR492, DOUGLAS_BMI1_TARGETS_DN, GOBP_MONOATOMIC_ION_HOMEOSTASIS, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, YAMAZAKI_TCEB3_TARGETS_UP, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_LATE_ENDOSOME_MEMBRANE, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, SCGGAAGY_ELK1_02

GO Biological Process (2): intracellular iron ion homeostasis (GO:0006879), transmembrane transport (GO:0055085)

GO Molecular Function (4): oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), transmembrane ascorbate ferrireductase activity (GO:0140571), protein binding (GO:0005515)

GO Cellular Component (7): nucleolus (GO:0005730), lysosomal membrane (GO:0005765), late endosome membrane (GO:0031902), lysosome (GO:0005764), endosome (GO:0005768), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
transport	1
cellular process	1
catalytic activity	1
cation binding	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on metal ions	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
lysosome	1
lytic vacuole membrane	1
late endosome	1
endosome membrane	1
lytic vacuole	1
endomembrane system	1
cytoplasmic vesicle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYB561A3	CYB561D2	O14569	571
CYB561A3	IPP	Q9Y573	560
CYB561A3	FRRS1	Q6ZNA5	478
CYB561A3	PIGL	Q9Y2B2	403
CYB561A3	POLR3H	Q9Y535	398
CYB561A3	SERAC1	Q96JX3	383
CYB561A3	STEAP3	Q658P3	380
CYB561A3	STEAP2	Q8NFT2	379
CYB561A3	FAM53C	Q9NYF3	378
CYB561A3	NT5DC4	Q86YG4	376
CYB561A3	INSYN1	Q2T9L4	350
CYB561A3	PPRC1	Q5VV67	348
CYB561A3	GFM1	Q96RP9	342
CYB561A3	UQCRB	P14927	340
CYB561A3	HERPUD2	Q9BSE4	333

IntAct

70 interactions, top by confidence:

A	B	Type	Score
CYB561A3	RNF5	psi-mi:“MI:0915”(physical association)	0.720
CYB561A3	CD40	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	LAPTM4B	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CREB3L3	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	RNF185	psi-mi:“MI:0915”(physical association)	0.560
	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	HERPUD2	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	GPR101	psi-mi:“MI:0915”(physical association)	0.560
AQP6	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	GPR152	psi-mi:“MI:0915”(physical association)	0.560
CD40	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CLDN7	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	GPX8	psi-mi:“MI:0915”(physical association)	0.560
CLDN5	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
LAPTM4B	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CD79A	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
CYB561A3	AGPAT5	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
PVR	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560
SHISAL1	CYB561A3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (25): CYB561A3 (Two-hybrid), AOC1 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid), CYB561A3 (Two-hybrid)

ESM2 similar proteins: A2AE42, A3A9H6, A5D7C9, A5D9A7, A6NM10, B3SHH9, B5DFH9, B9EJG8, F1NZP5, O14569, P10897, P49447, P82352, Q08DE1, Q14714, Q148G2, Q3ZCD2, Q5E965, Q5ND56, Q5RCZ2, Q5U2W7, Q5ZJX0, Q60720, Q62147, Q641Y1, Q6GPL4, Q6P0C6, Q6P1H1, Q71RH2, Q7TNV1, Q80ZE4, Q86TG1, Q8BMD6, Q8C8S3, Q8IXF9, Q8N8Q1, Q8NBI2, Q8TBR7, Q8VHW3, Q8VHW7

Diamond homologs: A3A9H6, A3KPR5, A5D9A7, C4IYS8, P10897, P34465, P49447, Q503V1, Q5CZL8, Q5RAJ4, Q5RCZ2, Q5RKJ2, Q5U2W7, Q60720, Q67ZF6, Q6DDR3, Q6I681, Q6P1H1, Q7XMK3, Q8L856, Q8NBI2, Q91577, Q925G2, Q95204, Q95245, Q9C540, Q9SWS1, Q53TN4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1778 predictions. Top by Δscore:

Variant	Effect	Δscore
11:61350985:CCATA:C	donor_loss	1.0000
11:61350986:CATAC:C	donor_loss	1.0000
11:61350987:ATACC:A	donor_loss	1.0000
11:61350988:TACCT:T	donor_loss	1.0000
11:61350989:A:T	donor_loss	1.0000
11:61350990:C:CA	donor_loss	1.0000
11:61350990:CCTGT:C	donor_gain	1.0000
11:61351143:TTTTC:T	acceptor_gain	1.0000
11:61351144:TTTC:T	acceptor_gain	1.0000
11:61351145:TTC:T	acceptor_gain	1.0000
11:61351146:TCC:T	acceptor_loss	1.0000
11:61351148:C:CC	acceptor_gain	1.0000
11:61351148:CTGAA:C	acceptor_loss	1.0000
11:61351149:T:G	acceptor_loss	1.0000
11:61352984:CAAA:C	donor_gain	1.0000
11:61353779:CCCA:C	donor_loss	1.0000
11:61353780:CCAC:C	donor_loss	1.0000
11:61353781:CACCT:C	donor_loss	1.0000
11:61353782:A:C	donor_loss	1.0000
11:61356524:A:AC	donor_gain	1.0000
11:61356524:ACTC:A	donor_loss	1.0000
11:61356525:C:CC	donor_gain	1.0000
11:61356527:CACCA:C	donor_loss	1.0000
11:61356528:ACC:A	donor_loss	1.0000
11:61356529:C:A	donor_loss	1.0000
11:61356529:CCA:C	donor_gain	1.0000
11:61356545:C:CT	donor_gain	1.0000
11:61356546:C:CT	donor_gain	1.0000
11:61356724:CACTC:C	acceptor_gain	1.0000
11:61357824:CTCAC:C	acceptor_gain	1.0000

AlphaMissense

1564 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61353116:G:C	F139L	0.989
11:61353116:G:T	F139L	0.989
11:61353118:A:G	F139L	0.989
11:61353823:G:C	S118R	0.988
11:61353823:G:T	S118R	0.988
11:61353825:T:G	S118R	0.988
11:61356575:G:C	H47D	0.987
11:61353139:A:G	W132R	0.986
11:61353139:A:T	W132R	0.986
11:61353828:G:C	H117D	0.986
11:61356582:G:C	F44L	0.986
11:61356582:G:T	F44L	0.986
11:61356584:A:G	F44L	0.986
11:61353888:C:A	G97W	0.984
11:61353937:T:A	K80N	0.984
11:61353937:T:G	K80N	0.984
11:61351093:G:C	N201K	0.981
11:61351093:G:T	N201K	0.981
11:61353930:G:C	H83D	0.981
11:61353871:A:C	F102L	0.980
11:61353871:A:T	F102L	0.980
11:61353873:A:G	F102L	0.980
11:61351086:C:A	G204W	0.979
11:61353793:G:C	F128L	0.978
11:61353793:G:T	F128L	0.978
11:61353795:A:G	F128L	0.978
11:61353822:A:G	W119R	0.977
11:61353822:A:T	W119R	0.977
11:61353826:G:C	H117Q	0.977
11:61353826:G:T	H117Q	0.977

dbSNP variants (sampled 300 via entrez): RS1000105849 (11:61363993 C>G), RS1000112921 (11:61358048 G>T), RS1000229450 (11:61358264 A>G), RS1000342176 (11:61358555 A>G), RS1000383192 (11:61354302 A>G), RS1001022368 (11:61351520 A>C,G), RS1001554190 (11:61363359 A>G), RS1001596818 (11:61353505 C>T), RS1001606679 (11:61363009 G>C), RS1001835763 (11:61352342 T>C), RS1001846519 (11:61351741 T>C), RS1001930716 (11:61352031 G>A), RS1001962576 (11:61352051 G>A), RS1002500617 (11:61362705 A>G), RS1002560474 (11:61362199 A>C)

Disease associations

OMIM: gene MIM:618757 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	4
sodium arsenite	increases abundance, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	increases expression	1

Clinical trials (associated diseases)

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