METTL21C

Summary

METTL21C (methyltransferase 21C, AARS1 lysine, HGNC:33717) is a protein-coding gene on chromosome 13q33.1, encoding Protein-lysine methyltransferase METTL21C (Q5VZV1). Protein-lysine N-methyltransferase using S-adenosyl-L-methionine as methyl donor.

Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Located in cytoplasm and nucleus. Part of protein-containing complex.

Source: NCBI Gene 196541 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 49 total — 1 pathogenic
• MANE Select transcript: NM_001010977

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33717
Approved symbol	METTL21C
Name	methyltransferase 21C, AARS1 lysine
Location	13q33.1
Locus type	gene with protein product
Status	Approved
Aliases	LOC196541
Ensembl gene	ENSG00000139780
Ensembl biotype	protein_coding
OMIM	615259
Entrez	196541

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000267273

RefSeq mRNA: 1 — MANE Select: NM_001010977 NM_001010977

CCDS: CCDS32003

Canonical transcript exons

ENST00000267273 — 4 exons

Exon	Start	End
ENSE00000940137	102686940	102687057
ENSE00000940138	102685747	102686425
ENSE00001381557	102690813	102690964
ENSE00001469227	102694369	102695044

Expression profiles

Bgee: expression breadth broad, 65 present calls, max score 93.77.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.82	gold quality
deltoid	UBERON:0001476	83.90	gold quality
corpus epididymis	UBERON:0004359	83.27	gold quality
cauda epididymis	UBERON:0004360	79.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.10	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.91	gold quality
biceps brachii	UBERON:0001507	76.33	gold quality
tibialis anterior	UBERON:0001385	71.16	silver quality
muscle of leg	UBERON:0001383	66.15	gold quality
gastrocnemius	UBERON:0001388	66.10	gold quality
skeletal muscle tissue	UBERON:0001134	62.94	gold quality
muscle tissue	UBERON:0002385	61.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	59.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	57.32	gold quality
right frontal lobe	UBERON:0002810	56.54	gold quality
pancreatic ductal cell	CL:0002079	55.58	silver quality
placenta	UBERON:0001987	55.43	gold quality
prefrontal cortex	UBERON:0000451	55.24	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
epithelial cell of pancreas	CL:0000083	54.11	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
frontal cortex	UBERON:0001870	53.51	gold quality
smooth muscle tissue	UBERON:0001135	52.99	gold quality
neocortex	UBERON:0001950	52.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	51.31	gold quality
anterior cingulate cortex	UBERON:0009835	51.20	gold quality
myocardium	UBERON:0002349	50.25	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.62
E-MTAB-6142	no	0.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting METTL21C, 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-548AN	99.97	70.91	2817
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-320A-5P	98.88	66.75	1248
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-375-3P	97.91	65.12	483
HSA-MIR-22-5P	97.67	68.92	1355

Literature-anchored findings (GeneRIF, showing 1)

• the polymorphisms and haplotypes of METTL21C contribute to the peak bone mineral density and total fat mass in Chinese males. (PMID:27628047)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mettl21cb	ENSDARG00000055437
danio_rerio	mettl21ca	ENSDARG00000078878
mus_musculus	Mettl21c	ENSMUSG00000047343
rattus_norvegicus	Mettl21c	ENSRNOG00000011591

Paralogs (5): VCPKMT (ENSG00000100483), EEF1AKMT3 (ENSG00000123427), METTL21A (ENSG00000144401), METTL23 (ENSG00000181038), METTL21EP (ENSG00000250878)

Protein

Protein identifiers

Protein-lysine methyltransferase METTL21C — Q5VZV1 (reviewed: Q5VZV1)

Alternative names: Methyltransferase-like protein 21C

All UniProt accessions (1): Q5VZV1

UniProt curated annotations — full annotation on UniProt →

Function. Protein-lysine N-methyltransferase using S-adenosyl-L-methionine as methyl donor. Mono-di and trimethylates ‘Lys-943’ of AARS1.

Subunit / interactions. Interacts with members of the heat shock protein 70 families; these proteins may possibly be methylation substrates for the enzyme.

Subcellular location. Nucleus. Cytoplasm.

Similarity. Belongs to the methyltransferase superfamily. METTL21 family.

RefSeq proteins (1): NP_001010977* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019410	Methyltransf_16	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF10294

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl-[protein] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:51736)
• N(6)-methyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54196)
• N(6),N(6)-dimethyl-L-lysyl-[protein] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:54200)

UniProt features (36 total): strand 11, helix 8, binding site 5, turn 4, mutagenesis site 3, sequence variant 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4MTL	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VZV1-F1	86.01	0.73

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 (5): 92; 120–122; 141; 172; 193

Mutagenesis-validated functional residues (3):

Position	Phenotype
92	abolishes methyltransferase activity; when associated with a-197.
141	abolishes methyltransferase activity.
197	abolishes methyltransferase activity; when associated with a-92.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_CORTICOSTEROID_STIMULUS, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_MAINTENANCE_OF_LOCATION, GOBP_RESPONSE_TO_KETONE, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT

GO Biological Process (7): protein methylation (GO:0006479), skeletal muscle tissue development (GO:0007519), hormone-mediated apoptotic signaling pathway (GO:0008628), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), peptidyl-lysine methylation (GO:0018022), cellular response to dexamethasone stimulus (GO:0071549), methylation (GO:0032259)

GO Molecular Function (6): protein methyltransferase activity (GO:0008276), protein-lysine N-methyltransferase activity (GO:0016279), heat shock protein binding (GO:0031072), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein alkylation	1
macromolecule methylation	1
striated muscle tissue development	1
skeletal muscle organ development	1
hormone-mediated signaling pathway	1
apoptotic signaling pathway	1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of release of sequestered calcium ion into cytosol	1
protein methylation	1
peptidyl-lysine modification	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
metabolic process	1
methyltransferase activity	1
catalytic activity, acting on a protein	1
protein methyltransferase activity	1
lysine N-methyltransferase activity	1
protein binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cellular_component	1

Protein interactions and networks

STRING

675 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
METTL21C	EEF1AKMT2	Q5JPI9	757
METTL21C	METTL2B	Q6P1Q9	691
METTL21C	METTL13	Q8N6R0	689
METTL21C	ETFBKMT	Q8IXQ9	648
METTL21C	EEF2KMT	Q96G04	622
METTL21C	METTL18	O95568	592
METTL21C	OR8U1	Q8NH10	591
METTL21C	METTL9	Q9H1A3	585
METTL21C	METTL25	Q8N6Q8	581
METTL21C	KIN	O60870	570
METTL21C	EEF1AKMT1	Q8WVE0	527
METTL21C	CAMKMT	Q7Z624	517
METTL21C	FAM187A	A6NFU0	516
METTL21C	NINL	Q9Y2I6	492
METTL21C	METTL24	Q5JXM2	487

IntAct

14 interactions, top by confidence:

A	B	Type	Score
ELOC	METTL21C	psi-mi:“MI:0915”(physical association)	0.780
METTL21C	ELOC	psi-mi:“MI:0915”(physical association)	0.780
METTL21C	BCKDK	psi-mi:“MI:0915”(physical association)	0.640
METTL21C	BCKDK	psi-mi:“MI:0914”(association)	0.640
BPIFC	METTL21C	psi-mi:“MI:0915”(physical association)	0.400
ELOC	METTL21C	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): METTL21C (Two-hybrid), BCKDK (Affinity Capture-MS), BCKDK (Affinity Capture-MS), TCEB1 (Two-hybrid), BCKDK (Affinity Capture-MS), METTL21C (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CARM1 (Affinity Capture-MS), CCDC88A (Affinity Capture-MS), CCT3 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS), GTF3C4 (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS)

ESM2 similar proteins: A2AA28, A2RRH5, A4FV42, A6NDL7, A7MCT6, B0K012, B2RYG8, D3YWP0, D3ZRW8, E1B8U2, J3S6Y1, P21964, P50747, Q0V8R7, Q1JP61, Q2TBI8, Q3SZD4, Q3U2J5, Q4VBE8, Q58DC7, Q5E9Y6, Q5RJL2, Q5VZV1, Q6DJF8, Q6GQ33, Q6P9U1, Q7Z624, Q80WC9, Q86XA0, Q8BNV1, Q8C436, Q8CDZ2, Q8IZ69, Q8N371, Q8R1C6, Q8WU66, Q920N2, Q96AZ1, Q96CB9, Q96RR1

Diamond homologs: A2AA28, A4FV42, A4FV98, A4IGU3, A6NDL7, A6QP81, A7IQW5, D3YWP0, P0CU27, P53970, Q28IN4, Q2KIJ2, Q58DC7, Q5BLD8, Q5RE14, Q5RJL2, Q5VZV1, Q6DJF8, Q86XA0, Q8BLU2, Q8C436, Q8CDZ2, Q8R1C6, Q8WXB1, Q96AZ1, Q9BUU2, Q9CQL0, Q9H867, F4JNX3, O14118, O95568, P40389, P47163, Q4KM84, Q55DL2, Q9CZ09, Q7S634, P0CP44, P0CP45, P64840

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
METTL21C	“up-regulates activity”	VCP	methylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	40
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4820199	NC_000013.10:g.102057928_104641357del	Pathogenic

SpliceAI

493 predictions. Top by Δscore:

Variant	Effect	Δscore
13:102686949:TGGC:T	donor_gain	1.0000
13:102690837:A:C	donor_gain	1.0000
13:102690870:T:A	donor_gain	1.0000
13:102694363:GGTTA:G	donor_loss	1.0000
13:102694364:GTTAC:G	donor_loss	1.0000
13:102694365:TTACC:T	donor_loss	1.0000
13:102694366:TACCT:T	donor_loss	1.0000
13:102686423:CTC:C	acceptor_gain	0.9900
13:102686424:TCCTA:T	acceptor_loss	0.9900
13:102686426:C:CA	acceptor_loss	0.9900
13:102686426:C:CC	acceptor_gain	0.9900
13:102686427:T:A	acceptor_loss	0.9900
13:102690811:ACC:A	donor_gain	0.9900
13:102690812:CCC:C	donor_gain	0.9900
13:102690824:C:CT	donor_gain	0.9900
13:102690850:T:TA	donor_gain	0.9900
13:102694368:CCTT:C	donor_gain	0.9900
13:102694381:C:A	donor_gain	0.9900
13:102686951:G:A	donor_gain	0.9800
13:102690825:C:CT	donor_gain	0.9800
13:102694302:A:AC	donor_gain	0.9800
13:102694303:C:CC	donor_gain	0.9800
13:102694380:C:CA	donor_gain	0.9800
13:102686424:TC:T	acceptor_gain	0.9700
13:102686425:CC:C	acceptor_gain	0.9700
13:102690841:T:A	donor_gain	0.9700
13:102690965:C:CC	acceptor_gain	0.9700
13:102694371:T:A	donor_gain	0.9600
13:102686519:AG:A	donor_gain	0.9300
13:102687326:G:C	donor_gain	0.9300

AlphaMissense

1716 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:102686312:A:G	W172R	0.997
13:102686312:A:T	W172R	0.997
13:102686165:A:G	W221R	0.994
13:102686165:A:T	W221R	0.994
13:102686149:C:A	R226M	0.993
13:102686969:C:T	G124D	0.993
13:102690821:A:G	W92R	0.993
13:102690821:A:T	W92R	0.993
13:102686127:A:C	F233L	0.992
13:102686127:A:T	F233L	0.992
13:102686129:A:G	F233L	0.992
13:102686149:C:G	R226T	0.992
13:102686310:C:A	W172C	0.992
13:102686310:C:G	W172C	0.992
13:102686239:A:T	V196D	0.991
13:102686245:T:A	D194V	0.990
13:102686380:A:G	L149P	0.990
13:102690815:C:A	G94W	0.990
13:102686128:A:G	F233S	0.989
13:102686148:C:A	R226S	0.988
13:102686148:C:G	R226S	0.988
13:102686251:G:T	A192D	0.988
13:102686975:C:T	G122E	0.986
13:102686246:C:G	D194H	0.985
13:102686257:A:T	V190D	0.985
13:102686317:A:G	L170P	0.985
13:102690848:A:G	S83P	0.985
13:102686138:C:G	D230H	0.984
13:102686410:G:T	A139E	0.984
13:102686981:C:T	G120D	0.984

dbSNP variants (sampled 300 via entrez): RS1000010905 (13:102704891 T>C), RS1000281160 (13:102700132 T>C), RS1000600457 (13:102690805 T>A,C), RS1000728480 (13:102696032 C>G,T), RS1000889512 (13:102701234 C>T), RS1000972632 (13:102691094 A>G), RS1000994477 (13:102688010 G>A), RS1001016177 (13:102706287 G>A,C,T), RS1001240080 (13:102688157 A>G), RS1001382267 (13:102700484 C>T), RS1001610377 (13:102695285 C>T), RS1001615720 (13:102701211 T>A), RS1001893390 (13:102705703 C>A,T), RS1001955342 (13:102691221 G>A), RS1002074572 (13:102691153 T>C)

Disease associations

OMIM: gene MIM:615259 | disease phenotypes: MIM:193003

GenCC curated gene-disease

Mondo (1): spinocerebellar ataxia 27A (MONDO:0008654)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002709_11	Electroencephalogram traits	2.000000e-06
GCST004641_3	Borderline personality disorder	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0006870	alpha wave measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
Aflatoxin B1	increases methylation	2
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
Methapyrilene	increases methylation	1

Clinical trials (associated diseases)

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