HEMK2

Summary

HEMK2 (HemK methyltransferase 2, ETF1 glutamine and histone H4 lysine, HGNC:16021) is a protein-coding gene on chromosome 21q21.3, encoding Methyltransferase HEMK2 (Q9Y5N5). Methyltransferase that can methylate proteins and, to a lower extent, arsenic. It is a selective cancer dependency (DepMap: 52.4% of cell lines).

This gene encodes an N(6)-adenine-specific DNA methyltransferase. The encoded enzyme may be involved in the methylation of release factor I during translation termination. This enzyme is also involved in converting the arsenic metabolite monomethylarsonous acid to the less toxic dimethylarsonic acid. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 11.

Source: NCBI Gene 29104 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 40 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 52.4% of screened cell lines
• MANE Select transcript: NM_013240

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16021
Approved symbol	HEMK2
Name	HemK methyltransferase 2, ETF1 glutamine and histone H4 lysine
Location	21q21.3
Locus type	gene with protein product
Status	Approved
Aliases	PRED28, N6AMT, MTQ2, KMT9, PrmC
Ensembl gene	ENSG00000156239
Ensembl biotype	protein_coding
OMIM	614553
Entrez	29104

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000303775, ENST00000351429, ENST00000460212, ENST00000873666, ENST00000922530

RefSeq mRNA: 2 — MANE Select: NM_013240 NM_013240, NM_182749

CCDS: CCDS33525, CCDS33526

Canonical transcript exons

ENST00000303775 — 6 exons

Exon	Start	End
ENSE00001025338	28879870	28879953
ENSE00001025339	28882985	28883071
ENSE00001025343	28882160	28882250
ENSE00001025345	28878192	28878333
ENSE00001137404	28872191	28876491
ENSE00003845669	28885212	28885367

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 84.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9605 / max 260.2594, expressed in 1750 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190057	11.9605	1750

Top tissues by expression

260 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	84.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.91	gold quality
ventricular zone	UBERON:0003053	82.09	gold quality
right uterine tube	UBERON:0001302	82.03	gold quality
apex of heart	UBERON:0002098	81.39	gold quality
left ovary	UBERON:0002119	80.49	gold quality
right adrenal gland	UBERON:0001233	80.40	gold quality
right adrenal gland cortex	UBERON:0035827	80.22	gold quality
ganglionic eminence	UBERON:0004023	80.03	gold quality
body of uterus	UBERON:0009853	79.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.77	gold quality
cortical plate	UBERON:0005343	79.45	gold quality
ascending aorta	UBERON:0001496	79.41	gold quality
right ovary	UBERON:0002118	79.37	gold quality
left adrenal gland	UBERON:0001234	79.34	gold quality
thoracic aorta	UBERON:0001515	79.32	gold quality
adrenal tissue	UBERON:0018303	79.23	gold quality
tibial nerve	UBERON:0001323	79.20	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.01	gold quality
lower esophagus	UBERON:0013473	78.99	gold quality
left adrenal gland cortex	UBERON:0035825	78.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.87	gold quality
sural nerve	UBERON:0015488	78.28	gold quality
right coronary artery	UBERON:0001625	78.24	gold quality
aorta	UBERON:0000947	78.22	gold quality
left coronary artery	UBERON:0001626	78.12	gold quality
endocervix	UBERON:0000458	78.08	gold quality
descending thoracic aorta	UBERON:0002345	78.03	gold quality
heart left ventricle	UBERON:0002084	77.82	gold quality
popliteal artery	UBERON:0002250	77.70	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting HEMK2, 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-4789-3P	99.99	70.75	2484
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-1295B-3P	96.68	66.11	276
HSA-MIR-4515	95.70	65.73	716
HSA-MIR-1269A	92.75	64.61	542
HSA-MIR-1269B	92.75	64.73	538

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 52.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• The human HemK2 protein methylates human and yeast eRF1.eRF3.GTP in vitro, and that the methyltransferase catalytic subunit can complement the growth defect of yeast strains deleted for mtq2. (PMID:18539146)
• N6AMT1 converted monomethylarsonous acid to dimethylarsonic acid when overexpressed in UROtsa human urothelial cells. It is expressed in many human tissues at variable levels, supporting a potential participation in arsenic metabolism in vivo. (PMID:21193388)
• Five N6AMT1 single nucleotide polymorphisms and two N6AMT1 haplotypes were significantly associated with the percentage of methylarsonic acid in urine, even after adjusting for arsenic (+3 oxidation state) methyltransferase haplotype. (PMID:23665909)
• combined effect of N6AMT1 haplotype 2_GGCCAT and As3MT haplotype 2_GCAC showed consistence with the additive significance of each haplotype on % iAs: the mean was 5.47% and 9.36% for carriers with both and null haplotypes, respectively (PMID:27637898)
• AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile, were examined. (PMID:28640505)
• The abundance of 6mA was significantly lower in cancers, accompanied by decreased N6AMT1 and increased ALKBH1 levels, and downregulation of 6mA modification levels promoted tumorigenesis. Collectively, Results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis. (PMID:30017583)
• data link H4K12 methylation with KMT9-dependent regulation of androgen-independent prostate tumor cell proliferation, thereby providing a promising paradigm for the treatment of castration-resistant prostate cancer (PMID:31061526)
• The down-regulation of TRMT112 does not affect the N6AMT1 protein levels in cells, suggesting that the two proteins of TRMT112 network, WBSCR22 and N6AMT1, are differently regulated by their common cofactor. (PMID:31466382)
• Structural insight into HEMK2-TRMT112-mediated glutamine methylation. (PMID:32969463)
• KMT9 Controls Stemness and Growth of Colorectal Cancer. (PMID:34737213)
• Reducing N6AMT1-mediated 6mA DNA modification promotes breast tumor progression via transcriptional repressing cell cycle inhibitors. (PMID:35256595)
• Arsenic metabolism, N6AMT1 and AS3MT single nucleotide polymorphisms, and their interaction on gestational diabetes mellitus in Chinese pregnant women. (PMID:36681142)
• Distinct specificities of the HEMK2 protein methyltransferase in methylation of glutamine and lysine residues. (PMID:38284488)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	n6amt1	ENSDARG00000115421
mus_musculus	N6amt1	ENSMUSG00000044442
rattus_norvegicus	N6amt1	ENSRNOG00000001603
drosophila_melanogaster	HemK2	FBGN0031454
caenorhabditis_elegans		WBGENE00016341

Paralogs (2): HEMK1 (ENSG00000114735), ETFBKMT (ENSG00000139160)

Protein

Protein identifiers

Methyltransferase HEMK2 — Q9Y5N5 (reviewed: Q9Y5N5)

Alternative names: HemK methyltransferase family member 2, Lysine N-methyltransferase 9, Methylarsonite methyltransferase N6AMT1, Methyltransferase N6AMT1, Protein N(5)-glutamine methyltransferase

All UniProt accessions (1): Q9Y5N5

UniProt curated annotations — full annotation on UniProt →

Function. Methyltransferase that can methylate proteins and, to a lower extent, arsenic. Catalytic subunit of a heterodimer with TRMT112, which monomethylates ‘Lys-12’ of histone H4 (H4K12me1), a modification present at the promoters of numerous genes encoding cell cycle regulators. Catalytic subunit of a heterodimer with TRMT112, which catalyzes N5-methylation of Glu residue of proteins with a Gly-Gln-Xaa-Xaa-Xaa-Arg motif. Methylates ETF1 on ‘Gln-185’; ETF1 needs to be complexed to ERF3 in its GTP-bound form to be efficiently methylated. May also play a role in the modulation of arsenic-induced toxicity by mediating the conversion of monomethylarsonous acid (3+) into the less toxic dimethylarsonic acid. It however only plays a limited role in arsenic metabolism compared with AS3MT.

Subunit / interactions. Heterodimer; heterodimerization with TRMT112 is required for S-adenosyl-L-methionine-binding. Does not interact with TRMT112.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed, with highest expression in parathyroid and pituitary glands, followed by adrenal gland and kidney, and lowest expression in leukocytes and mammary gland.

Post-translational modifications. Ubiquitinated, leading to its degradation by the proteasome. Ubiquitinated, leading to its degradation by the proteasome.

Similarity. Belongs to the eukaryotic/archaeal PrmC-related family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5N5-1	1, Alpha, N6AMT1iso1	yes
Q9Y5N5-2	2, Beta, N6AMT1iso2

RefSeq proteins (2): NP_037372, NP_877426 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002052	DNA_methylase_N6_adenine_CS	Conserved_site
IPR004557	PrmC-related	Family
IPR007848	Small_mtfrase_dom	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR052190	Mtq2-like	Family

Pfam: PF05175

Enzyme classification (BRENDA):

• EC 2.1.1.137 — arsenite methyltransferase (BRENDA: 54 organisms, 46 substrates, 14 inhibitors, 39 Km, 0 kcat entries)
• EC 2.1.1.72 — site-specific DNA-methyltransferase (adenine-specific) (BRENDA: 94 organisms, 133 substrates, 57 inhibitors, 77 Km, 82 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DNA ADENINE	—	38
ARSENITE	0.0012–0.0185	27
DOUBLE STRANDED DNA ADENINE	—	11
S-ADENOSYL-L-METHIONINE	0.0001–0.0122	11
S-ADENOSYL-L-METHIONINE	0.0031–0.0512	8
METHYLARSONATE	0.0007–0.003	4
ADENINE IN DNA	—	2
ADENINE IN T4 GT- DAM- DNA	—	1
SINGLE STRANDED DNA ADENINE	0.0003	1
T7 DNA ADENINE	—	1
OLIGODEOXYNUCLEOTIDE DUPLEXES 5’-GATC/5’-GATC	—	0

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl-[histone] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl-[histone] + S-adenosyl-L-homocysteine + H(+) (RHEA:10024)
• methylarsonous acid + S-adenosyl-L-methionine = dimethylarsinate + S-adenosyl-L-homocysteine + 2 H(+) (RHEA:11684)
• L-glutaminyl-[protein] + S-adenosyl-L-methionine = N(5)-methyl-L-glutaminyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:57452)

UniProt features (60 total): mutagenesis site 18, binding site 15, helix 13, strand 7, sequence variant 3, turn 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
8QDG	X-RAY DIFFRACTION	1.39
9FKW	X-RAY DIFFRACTION	1.39
9FL5	X-RAY DIFFRACTION	1.39
8CNC	X-RAY DIFFRACTION	1.46
8QDI	X-RAY DIFFRACTION	1.47
9FKV	X-RAY DIFFRACTION	1.47
9FKM	X-RAY DIFFRACTION	1.5
9FKG	X-RAY DIFFRACTION	1.59
9FIM	X-RAY DIFFRACTION	1.6
9FKE	X-RAY DIFFRACTION	1.6
9FL4	X-RAY DIFFRACTION	1.7
6KHS	X-RAY DIFFRACTION	1.9
6H1E	X-RAY DIFFRACTION	1.9
6H1D	X-RAY DIFFRACTION	1.94
6KMR	X-RAY DIFFRACTION	2
6K0X	X-RAY DIFFRACTION	2.2
6PED	X-RAY DIFFRACTION	2.3
6KMS	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5N5-F1	94.71	0.89

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 (15): 29; 103; 104; 104; 122; 122; 122; 29; 51; 51; 53; 53 …

Mutagenesis-validated functional residues (18):

Position	Phenotype
24	reduced protein n(5)-glutamine methyltransferase activity.
27	abolished protein n(5)-glutamine methyltransferase activity.
28	abolished protein n(5)-glutamine methyltransferase activity.
51	abolished protein n(5)-glutamine methyltransferase activity.
72	strongly reduced protein n(5)-glutamine methyltransferase activity.
77	abolished protein n(5)-glutamine methyltransferase activity.
78	abolished protein n(5)-glutamine methyltransferase activity.
83	strongly reduced protein n(5)-glutamine methyltransferase activity.
103	abolished protein n(5)-glutamine methyltransferase activity. abolished histone-lysine methyltransferase activity.
108	strongly reduced protein n(5)-glutamine methyltransferase activity.
122–125	abolished dna methyltransferase activity.
122	abolished protein n(5)-glutamine methyltransferase activity. abolished histone-lysine methyltransferase activity.
125	abolished protein n(5)-glutamine methyltransferase activity without affecting histone-lysine methyltransferase activity.
132	abolished protein n(5)-glutamine methyltransferase activity.
139	reduced protein n(5)-glutamine methyltransferase activity.
154	slightly reduced protein n(5)-glutamine methyltransferase activity.
176	abolished protein n(5)-glutamine methyltransferase activity.
204	abolished protein n(5)-glutamine methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-156581	Methylation
R-HSA-72764	Eukaryotic Translation Termination
R-HSA-1430728	Metabolism
R-HSA-156580	Phase II - Conjugation of compounds
R-HSA-211859	Biological oxidations
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 146 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MODULE_77, GOBP_GROWTH, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_POSITIVE_REGULATION_OF_CELL_GROWTH, BRN2_01, GOBP_TOXIN_METABOLIC_PROCESS, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_GROWTH, DOUGLAS_BMI1_TARGETS_DN, MODULE_48

GO Biological Process (8): toxin metabolic process (GO:0009404), peptidyl-glutamine methylation (GO:0018364), arsonoacetate metabolic process (GO:0018872), positive regulation of cell growth (GO:0030307), methylation (GO:0032259), negative regulation of gene expression, epigenetic (GO:0045814), transcription initiation-coupled chromatin remodeling (GO:0045815), chromatin organization (GO:0006325)

GO Molecular Function (12): nucleic acid binding (GO:0003676), protein methyltransferase activity (GO:0008276), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), site-specific DNA-methyltransferase (adenine-specific) activity (GO:0009007), arsenite methyltransferase activity (GO:0030791), protein-glutamine N-methyltransferase activity (GO:0036009), histone H4K12 methyltransferase activity (GO:0140984), S-adenosyl-L-methionine binding (GO:1904047), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), protein-containing complex (GO:0032991), eRF1 methyltransferase complex (GO:0035657)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Phase II - Conjugation of compounds	1
Translation	1
Biological oxidations	1
Metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
S-adenosylmethionine-dependent methyltransferase activity	3
binding	2
methyltransferase activity	2
protein methyltransferase activity	2
secondary metabolic process	1
protein methylation	1
xenobiotic metabolic process	1
carboxylic acid metabolic process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
metabolic process	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of gene expression, epigenetic	1
cellular component organization	1
catalytic activity, acting on a protein	1
DNA-methyltransferase activity	1
N-methyltransferase activity	1
protein-lysine N-methyltransferase activity	1
histone H4 methyltransferase activity	1
cation binding	1
sulfur compound binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
histone modifying activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1
cellular_component	1
methyltransferase complex	1

Protein interactions and networks

STRING

1506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEMK2	TRMT112	Q9UI30	980
HEMK2	TRMT11	Q7Z4G4	811
HEMK2	HEMK1	Q9Y5R4	811
HEMK2	BUD23	O43709	777
HEMK2	METTL4	Q8N3J2	734
HEMK2	ALKBH1	Q13686	709
HEMK2	ALKBH8	Q96BT7	696
HEMK2	ETF1	P46055	690
HEMK2	ALKBH4	Q9NXW9	666
HEMK2	AS3MT	Q9HBK9	611
HEMK2	METTL5	Q9NRN9	598
HEMK2	EVA1C	P58658	576
HEMK2	METTL3	Q86U44	572
HEMK2	WDR4	P57081	566
HEMK2	EEF1AKMT1	Q8WVE0	556

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TRMT112	BUD23	psi-mi:“MI:0914”(association)	0.910
TRMT112	HEMK2	psi-mi:“MI:0915”(physical association)	0.750
HEMK2	TRMT112	psi-mi:“MI:0915”(physical association)	0.750
HEMK2	TRMT112	psi-mi:“MI:0403”(colocalization)	0.750
Lyplal1	PARP10	psi-mi:“MI:0914”(association)	0.350
Cep85l	CLK2	psi-mi:“MI:0914”(association)	0.350
RNASEH2A	PHF20L1	psi-mi:“MI:0914”(association)	0.350
HSPA5	NCOR2	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): N6AMT1 (Affinity Capture-MS), N6AMT1 (Affinity Capture-MS), N6AMT1 (Affinity Capture-MS), N6AMT1 (Affinity Capture-MS), N6AMT1 (Positive Genetic), SUP45 (Biochemical Activity), SUP45 (Reconstituted Complex), SUP35 (Reconstituted Complex), N6AMT1 (Negative Genetic), N6AMT1 (Negative Genetic), N6AMT1 (Affinity Capture-MS), N6AMT1 (Proximity Label-MS), N6AMT1 (Proximity Label-MS), N6AMT1 (Proximity Label-MS), N6AMT1 (Proximity Label-MS)

ESM2 similar proteins: A0A6N3IN21, A3KCL7, A4IFH5, A7MBC0, A7MBI7, D3ZDK7, D3ZDM7, E1BNQ4, P09367, P10950, P11172, P13439, P17256, P20132, P24298, P25409, P31754, P46597, P50053, P97328, Q02974, Q03426, Q0VCW4, Q1JPD3, Q3B8E3, Q3TY86, Q3ZKN0, Q5BJJ5, Q5E9T8, Q5M7T9, Q5R514, Q5R824, Q5RD71, Q5RFE6, Q6PCB7, Q6SKR2, Q80W22, Q8CHP8, Q8CIM3, Q8HZJ0

Diamond homologs: A0R213, A1S8P4, A4QDG2, A4W687, A6H162, A8ALZ1, A9CG70, A9WBM9, B0B9D1, B2RK25, B8E004, C6Y2G0, O66506, O84027, P0A293, P0A294, P0ACC1, P0ACC2, P0DJB1, P39199, P39200, P40816, P45253, P45832, P72542, P74003, P75419, P9WHV2, P9WHV3, Q0WDE1, Q1II29, Q2FWE1, Q2RFW1, Q2RWE0, Q2S0V8, Q32DK7, Q32GZ5, Q3J2B7, Q49404, Q5E3U5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
N6AMT1	“form complex”	“N6AMT1-TRM112 methyltransferase complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2684912	GRCh37/hg19 21q21.1-22.11(chr21:20408138-32852758)x3	Pathogenic

SpliceAI

717 predictions. Top by Δscore:

Variant	Effect	Δscore
21:28882154:TCTTA:T	donor_loss	1.0000
21:28882155:CTTA:C	donor_loss	1.0000
21:28882156:TTA:T	donor_loss	1.0000
21:28882157:TA:T	donor_loss	1.0000
21:28882158:A:AC	donor_gain	1.0000
21:28882158:A:T	donor_loss	1.0000
21:28882159:C:CC	donor_gain	1.0000
21:28882248:CAC:C	acceptor_gain	1.0000
21:28882250:CCT:C	acceptor_loss	1.0000
21:28882251:C:CA	acceptor_loss	1.0000
21:28882252:T:G	acceptor_loss	1.0000
21:28882977:ATACT:A	donor_loss	1.0000
21:28882978:TACTT:T	donor_loss	1.0000
21:28882979:ACTTA:A	donor_loss	1.0000
21:28882980:CTT:C	donor_loss	1.0000
21:28882981:T:TC	donor_loss	1.0000
21:28882982:T:TC	donor_loss	1.0000
21:28882983:A:AC	donor_gain	1.0000
21:28882983:ACATG:A	donor_loss	1.0000
21:28882984:C:A	donor_loss	1.0000
21:28882984:C:CC	donor_gain	1.0000
21:28882984:CATGT:C	donor_gain	1.0000
21:28883067:CCACT:C	acceptor_gain	1.0000
21:28883068:CACTC:C	acceptor_gain	1.0000
21:28883069:ACTC:A	acceptor_loss	1.0000
21:28883070:CT:C	acceptor_gain	1.0000
21:28883070:CTCT:C	acceptor_loss	1.0000
21:28883071:TCTGA:T	acceptor_loss	1.0000
21:28883072:C:A	acceptor_loss	1.0000
21:28883072:C:CC	acceptor_gain	1.0000

AlphaMissense

1375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:28885264:C:G	D28H	0.991
21:28885256:A:C	F30L	0.990
21:28885256:A:T	F30L	0.990
21:28885258:A:G	F30L	0.990
21:28885263:T:A	D28V	0.990
21:28876407:A:T	V208D	0.989
21:28878199:G:C	N177K	0.987
21:28878199:G:T	N177K	0.987
21:28885263:T:G	D28A	0.987
21:28879900:A:C	N122K	0.986
21:28879900:A:T	N122K	0.986
21:28885262:G:C	D28E	0.986
21:28885262:G:T	D28E	0.986
21:28878284:C:G	R149P	0.985
21:28879903:A:C	F121L	0.985
21:28879903:A:T	F121L	0.985
21:28879905:A:G	F121L	0.985
21:28878287:C:A	G148V	0.983
21:28882243:C:G	D77H	0.983
21:28876398:A:G	F211S	0.982
21:28878287:C:T	G148D	0.982
21:28878303:C:G	A143P	0.982
21:28879902:T:C	N122D	0.982
21:28883036:C:T	G57D	0.982
21:28882249:A:G	C75R	0.981
21:28883020:G:C	F62L	0.981
21:28883020:G:T	F62L	0.981
21:28883022:A:G	F62L	0.981
21:28883042:C:T	G55E	0.980
21:28876404:A:G	L209P	0.979

dbSNP variants (sampled 300 via entrez): RS1000004135 (21:28788978 G>A,C), RS1000025002 (21:28784339 G>A), RS1000029063 (21:28647695 G>A), RS1000036582 (21:28733054 T>C,G), RS1000043813 (21:28811842 C>T), RS1000054979 (21:28706726 A>G), RS1000057348 (21:28827420 C>T), RS1000062969 (21:28868047 G>C), RS1000072946 (21:28836157 A>C,G), RS1000101929 (21:28655295 G>C), RS1000106039 (21:28660434 T>A), RS1000107448 (21:28612412 C>T), RS1000133328 (21:28699170 T>A), RS1000136818 (21:28778839 C>T), RS1000137569 (21:28808038 G>A)

Disease associations

OMIM: gene MIM:614553 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005998_27	Alanine transaminase levels	8.000000e-11
GCST007096_226	Pulse pressure	6.000000e-09
GCST007269_144	Pulse pressure	4.000000e-16
GCST007645_7	Estimated glomerular filtration rate after 1 year in renal transplantation (recipient effect)	1.000000e-06
GCST011352_13	Alanine aminotransferase levels	2.000000e-09
GCST90013407_148	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-19

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0005199	renal transplant outcome measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2254638	Efficacy	3	clopidogrel	Major Adverse Cardiac Events (MACE)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2254638	N6AMT1	3	0.00	1	clopidogrel

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases methylation, affects response to substance, affects metabolic processing, decreases response to substance	4
monomethylarsonous acid	increases metabolic processing, increases methylation, increases expression, affects response to substance, increases chemical synthesis	3
Valproic Acid	affects cotreatment, decreases expression	3
Nickel	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
monomethylarsonic acid	increases abundance	1
resorcinol	decreases expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	increases chemical synthesis, increases metabolic processing	1
abrine	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Arsenicals	affects response to substance	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Quercetin	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1K8	UROtsa N6AMT1	Transformed cell line	Female

Clinical trials (associated diseases)

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