BHMT

Summary

BHMT (betaine–homocysteine S-methyltransferase, HGNC:1047) is a protein-coding gene on chromosome 5q14.1, encoding Betaine–homocysteine S-methyltransferase 1 (Q93088). Involved in the regulation of homocysteine metabolism.

This gene encodes a cytosolic enzyme that catalyzes the conversion of betaine and homocysteine to dimethylglycine and methionine, respectively. Defects in this gene could lead to hyperhomocyst(e)inemia, but such a defect has not yet been observed.

Source: NCBI Gene 635 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 69 total
• Druggable target: yes
• MANE Select transcript: NM_001713

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1047
Approved symbol	BHMT
Name	betaine–homocysteine S-methyltransferase
Location	5q14.1
Locus type	gene with protein product
Status	Approved
Aliases	BHMT1
Ensembl gene	ENSG00000145692
Ensembl biotype	protein_coding
OMIM	602888
Entrez	635

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 4 retained_intron

ENST00000274353, ENST00000520335, ENST00000520703, ENST00000521279, ENST00000523508, ENST00000524080, ENST00000910525, ENST00000910526, ENST00000910527, ENST00000910528, ENST00000910529, ENST00000910530

RefSeq mRNA: 1 — MANE Select: NM_001713 NM_001713

CCDS: CCDS4046

Canonical transcript exons

ENST00000274353 — 8 exons

Exon	Start	End
ENSE00000971691	79119259	79119377
ENSE00000971692	79120350	79120541
ENSE00001953069	79130933	79132288
ENSE00002489331	79127755	79127983
ENSE00003477717	79121218	79121365
ENSE00003562328	79111809	79111918
ENSE00003590872	79126046	79126228
ENSE00003666278	79115767	79115899

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 98.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.0329 / max 933.3110, expressed in 148 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57231	3.0329	148

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	98.77	gold quality
kidney epithelium	UBERON:0004819	98.67	gold quality
renal glomerulus	UBERON:0000074	98.26	gold quality
right lobe of liver	UBERON:0001114	98.08	gold quality
metanephric glomerulus	UBERON:0004736	97.91	gold quality
adult mammalian kidney	UBERON:0000082	97.62	gold quality
liver	UBERON:0002107	97.34	gold quality
adult organism	UBERON:0007023	97.07	gold quality
kidney	UBERON:0002113	95.74	gold quality
cortex of kidney	UBERON:0001225	92.21	gold quality
metanephros	UBERON:0000081	91.07	gold quality
renal medulla	UBERON:0000362	89.41	gold quality
metanephros cortex	UBERON:0010533	85.29	gold quality
diaphragm	UBERON:0001103	84.46	gold quality
mucosa of urinary bladder	UBERON:0001259	83.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.72	gold quality
olfactory bulb	UBERON:0002264	77.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.77	gold quality
urinary bladder	UBERON:0001255	74.96	gold quality
hair follicle	UBERON:0002073	73.20	gold quality
type B pancreatic cell	CL:0000169	73.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	71.00	gold quality
lower esophagus	UBERON:0013473	70.91	gold quality
caput epididymis	UBERON:0004358	69.85	gold quality
cervix squamous epithelium	UBERON:0006922	68.87	gold quality
mucosa of stomach	UBERON:0001199	67.71	gold quality
body of stomach	UBERON:0001161	67.49	gold quality
colonic epithelium	UBERON:0000397	67.30	gold quality
vastus lateralis	UBERON:0001379	67.11	gold quality
quadriceps femoris	UBERON:0001377	66.86	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-135	yes	3451.57
E-CURD-119	yes	1210.73
E-HCAD-10	yes	35.99
E-MTAB-10553	yes	32.70
E-ANND-3	yes	11.06
E-MTAB-5061	no	3.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1, NFKB, RELA

miRNA regulators (miRDB)

45 targeting BHMT, 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-3646	100.00	73.56	5283
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-1911-3P	99.15	66.17	528
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-1-5P	98.70	68.66	1017

Literature-anchored findings (GeneRIF, showing 39)

• mutagenesis of the zinc-binding motif reveals that Gly 214 is essential (PMID:11883905)
• BHMT is a tetramer and its ability to methylate homocysteine is not affected by S-Adenosylmethionine (SAMe) (PMID:12071701)
• X-ray structures of human BHMT in its oxidized (Zn-free) and reduced (Zn-replete) forms, the latter in complex with the bisubstrate analog, S(delta-carboxybutyl)-L-homocysteine, were determined at resolutions of 2.15 A and 2.05 A (PMID:12220488)
• Study using intrinsic tryptophan fluorescence properties of BHMT demonstrates clearly that BHMT catalysis follows an ordered bi-bi mechanism and that betaine binding affinity is dependent on formation of the BHMT-homocysteine complex. (PMID:15122900)
• S-adenosylmethionine and methylthioadenosine downregulaate BHMT expression in HepG2 cells. (PMID:16953798)
• association between the homozygous mutant form of BHMT (742G–>A) polymorphism and increased risk for placental abruption. (PMID:17376725)
• The BHMT/betaine system directly protects hepatocytes from homocysteine-induced injury but not tunicamycin-induced injury, including an endoplasmic reticulum stress response, lipid accumulation, and cell death. (PMID:17705221)
• Experiments using the glutamate-cysteine ligase modifier subunit knockout mice Gclm(-/-), which are severely impaired in glutathione synthesis, show that BHMT activity is reduced about 75% in Gclm(-/-) compared to Gclm(+/+) mice. (PMID:18262489)
• Common genetic variation in BHMT and BHMT2 and functionally characterized BHMT SNPs. (PMID:18457970)
• betaine-homocysteine methyltransferase (BHMT) transgenic mice are resistant to alcohol or high methionine low folate diet -induced hyperhomocysteinemia and liver steatosis (PMID:18498552)
• The BHMT 742 A allele was associated with resuced all-cause mortality. (PMID:18708404)
• betaine-homocysteine methyltransferase gene (BHMT) rs3733890 polymorphism was associated with reduced breast cancer-specific mortality (hazard ratio, 0.64; 95% confidence interval, 0.42-0.97) (PMID:19635752)
• gene-gene interaction analysis revealed significant epistatic interaction of BHMT2 (rs673752), PEMT (rs12325817), and PCYT1A (rs712012) with maternal NCL/P susceptibility. (PMID:20662904)
• Three SNPs (rs41272270, rs16876512, and rs6875201), located 28kb upstream, in the 5’-UTR and in intron 1 of BHMT, respectively, were significantly correlated with both BHMT activity and protein levels. (PMID:21093336)
• Results might suggest the protective role of the BHMT 239Gln variant in cervical cancer incidence. (PMID:21349258)
• No significant level of association was found with cleft lip with or without cleft palate and BHMT variants. (PMID:21564312)
• This suggests that polymorphism rs3797546 in the BHMT gene may confer genetic risk of NSCL/P in a recessive manner. (PMID:21565678)
• The BHMT 742GA or AA genotypes associated with tobacco consumption (P = 0.016) increase the risk for head and neck squamous cell carcinoma. (PMID:21630102)
• A transcription variant of exon 4 of betaine-homocysteine methyltransferase (BHMT) produces a loss of function of BHMT in human hepatocarcinoma (PMID:22138536)
• Known common single-nucleotide polymorphisms in MTRR and BHMT genes may not be significant risk factors for cororonary artery disease. (PMID:22339686)
• Our study suggests that the polymorphism BHMT G742A may modulate the Down syndrome risk in Brazilian mothers. (PMID:22339736)
• Women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a Down Syndrome pregnancy. (PMID:23645037)
• Data suggest BHMT is activated by binding of potassium ions; role of potassium ions in BHMT appears to be structural; potassium ions facilitate specific binding of substrate homocysteine (rather than substrate betaine) to active site of the enzyme. (PMID:24895213)
• Study suggests BHMT holds considerable potential as a blood biomarker for acute liver injury. (PMID:25144858)
• Multiple SNPs in BHMT and BHMT2 were identified to be associated with the occurrence of infant obstructive heart defects and interaction effects with maternal use of folic acid supplements. (PMID:25846410)
• The faster evolutionary rate of BHMT2 overall suggests that selective constraints were reduced relative to BHMT. (PMID:26213999)
• low BHMT expression is correlated with aggressive malignant phenotype of HCC. Our data indicate that BHMT may serve as a novel prognostic marker for HCC. (PMID:26592251)
• In genotypic combination analysis considering PEMT -744GG/CHDH +432GG/BHMT +742GG as the reference combination, PEMT -744GC/CHDH +432GG/BHMT +742GG genotypic combination was significantly higher in mothers of a down syndrome child compared with that in control mothers with an odds ratio of 2.061 (95% CI: 1.10-3.86, P=0.0342). (PMID:27677362)
• It was concluded that during pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele. (PMID:27735840)
• BHMT (rs3733890) polymorphism showed no association with ALL. Hence this investigation needs further evaluation in larger sample size and effect of other SNPs, CNVs and miRNA’s is required to elucidate the role of BHMT gene in ALL development. (PMID:28582843)
• Our study suggested markers in BHMT/BHMT2 and DMGDH might affect the risk of NSCL/P through pairwise interaction. (PMID:29356306)
• It can be inferred from the data obtained that folate system genetic variants and mild hyperhomocysteimenia may affect ADHD associated traits by attenuating folate metabolism. (PMID:29407547)
• Associations between folate and choline intake, homocysteine metabolism, and genetic polymorphism of MTHFR, BHMT and PEMT in healthy pregnant Polish women. (PMID:31044529)
• Association of Betaine-Homocysteine S-Methyl Transferase (rs3797546 and rs3733890) polymorphisms with non-syndromic cleft lip/palate: A meta-analysis. (PMID:31451344)
• Lower levels of BHMT or CBS promoter total methylation might be associated with increased the risk of treatment failure. (PMID:31558761)
• Interaction analysis of gene variants related to one-carbon metabolism with chronic hepatitis B infection in Chinese patients. (PMID:33894044)
• The BHMT-betaine methylation pathway epigenetically modulates oligodendrocyte maturation. (PMID:33975330)
• BHMT polymorphism and susceptibility to PTE in Chinese patients. (PMID:37203835)
• Ribosomal modification protein rimK-like family member A activates betaine-homocysteine S-methyltransferase 1 to ameliorate hepatic steatosis. (PMID:39117631)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	bhmt	ENSDARG00000013430
mus_musculus	Bhmt1b	ENSMUSG00000069324
mus_musculus	Bhmt	ENSMUSG00000074768
rattus_norvegicus	Bhmt	ENSRNOG00000011200

Paralogs (4): MTR (ENSG00000116984), UROD (ENSG00000126088), BHMT2 (ENSG00000132840), MTHFR (ENSG00000177000)

Protein

Protein identifiers

Betaine–homocysteine S-methyltransferase 1 — Q93088 (reviewed: Q93088)

All UniProt accessions (3): E5RJH0, Q93088, V9HWA4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of homocysteine metabolism. Converts betaine and homocysteine to dimethylglycine and methionine, respectively. This reaction is also required for the irreversible oxidation of choline.

Subunit / interactions. Homotetramer.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Tissue specificity. Found exclusively in liver and kidney.

Cofactor. Binds 1 zinc ion per subunit.

Pathway. Amine and polyamine degradation; betaine degradation; sarcosine from betaine: step 1/2. Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (BhmT route): step 1/1.

RefSeq proteins (1): NP_001704* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003726	HCY_dom	Domain
IPR017226	BHMT-like	Family
IPR036589	HCY_dom_sf	Homologous_superfamily
IPR051524	BHMT	Family

Pfam: PF02574

Enzyme classification (BRENDA):

• EC 2.1.1.5 — betaine-homocysteine S-methyltransferase (BRENDA: 13 organisms, 22 substrates, 105 inhibitors, 56 Km, 37 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BETAINE	0.002–2.4	23
L-HOMOCYSTEINE	0.004–2.3	23
S-METHYL-L-METHIONINE	0.76–3.4	4
DIMETHYLACETOTHETIN	0.155	1
DL-HOMOCYSTEINE	0.008	1
GLYCINEBETAINE	4.3	1
L-ASP	10	1

Catalyzed reactions (Rhea), 1 shown:

• L-homocysteine + glycine betaine = N,N-dimethylglycine + L-methionine (RHEA:22336)

UniProt features (53 total): helix 20, strand 8, modified residue 7, mutagenesis site 7, turn 4, binding site 3, sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4M3P	X-RAY DIFFRACTION	1.9
1LT8	X-RAY DIFFRACTION	2.05
1LT7	X-RAY DIFFRACTION	2.15
8D45	ELECTRON MICROSCOPY	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93088-F1	92.62	0.79

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 (3): 217; 299; 300

Post-translational modifications (7): 340, 377, 40, 93, 232, 241, 330

Mutagenesis-validated functional residues (7):

Position	Phenotype
216	decreases the catalytic efficiency.
217	impairs zinc ion binding. loss of catalytic activity.
220	has no significant effect on catalytic activity.
299	impairs zinc ion binding. loss of catalytic activity.
300	impairs zinc ion binding. loss of catalytic activity.
303	has no significant effect on catalytic activity.
306	has no significant effect on catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1614635	Sulfur amino acid metabolism
R-HSA-6798163	Choline catabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 133 (showing top): MODULE_571, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, HSIAO_LIVER_SPECIFIC_GENES

GO Biological Process (9): protein methylation (GO:0006479), amino-acid betaine metabolic process (GO:0006577), amino-acid betaine catabolic process (GO:0006579), obsolete regulation of homocysteine metabolic process (GO:0050666), ‘de novo’ L-methionine biosynthetic process (GO:0071266), L-methionine salvage (GO:0071267), modified amino acid metabolic process (GO:0006575), obsolete methionine biosynthetic process (GO:0009086), methylation (GO:0032259)

GO Molecular Function (6): zinc ion binding (GO:0008270), betaine-homocysteine S-methyltransferase activity (GO:0047150), methyltransferase activity (GO:0008168), S-methyltransferase activity (GO:0008172), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	2
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-methionine biosynthetic process	2
metabolic process	2
cellular anatomical structure	2
protein alkylation	1
macromolecule methylation	1
modified amino acid metabolic process	1
amino-acid betaine metabolic process	1
modified amino acid catabolic process	1
amino acid salvage	1
transition metal ion binding	1
S-methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1694 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BHMT	DMGDH	Q9UI17	865
BHMT	MTHFR	P42898	850
BHMT	H7C2H4	H7C2H4	834
BHMT	P0DN79	P0DN79	834
BHMT	GNMT	Q14749	830
BHMT	AHCY	P23526	816
BHMT	MTRR	Q9UBK8	800
BHMT	CTH	P32929	783
BHMT	MAT1A	Q00266	778
BHMT	SHMT1	P34896	775
BHMT	MTHFD1	P11586	748
BHMT	CHDH	Q8NE62	744
BHMT	PEMT	Q9UBM1	734
BHMT	SARDH	Q9UL12	712
BHMT	SHMT2	P34897	687

IntAct

12 interactions, top by confidence:

A	B	Type	Score
BHMT	BHMT	psi-mi:“MI:0915”(physical association)	0.550
BHMT	BHMT2	psi-mi:“MI:0914”(association)	0.530
BHMT	BHMT	psi-mi:“MI:0407”(direct interaction)	0.440
BBS1	BHMT	psi-mi:“MI:0915”(physical association)	0.370
BBS4	BHMT	psi-mi:“MI:0915”(physical association)	0.370
BBS2	BHMT	psi-mi:“MI:0915”(physical association)	0.370
BHMT	ALG9	psi-mi:“MI:0915”(physical association)	0.370
LAMTOR3	BHMT	psi-mi:“MI:0915”(physical association)	0.370
MREG	SPAG9	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): BHMT (Two-hybrid), BHMT (Two-hybrid), BHMT (Affinity Capture-MS), BHMT (Affinity Capture-MS), BHMT (Affinity Capture-MS), BHMT (Two-hybrid), BHMT2 (Affinity Capture-MS), MTMR6 (Affinity Capture-MS), BHMT (Co-crystal Structure), BHMT (Affinity Capture-MS), BHMT (Affinity Capture-MS), MTMR6 (Affinity Capture-MS), BHMT2 (Affinity Capture-MS), BHMT (Two-hybrid), BHMT (Two-hybrid)

ESM2 similar proteins: A7M6E7, B8BJ39, B8BM17, B9I2J6, B9N1F9, O09171, O22216, O22718, O35490, O80526, O89000, P11029, P11497, P28173, P35433, Q01217, Q06203, Q12882, Q13085, Q15024, Q28007, Q28559, Q28943, Q2QNG7, Q2QXR8, Q2QZ86, Q2RAK2, Q3T0V9, Q5I597, Q5M8Z0, Q5R895, Q5RFG2, Q5SWU9, Q5XGM3, Q5XGS8, Q6NYG8, Q8CHR6, Q8CIH9, Q8IX04, Q8S0G4

Diamond homologs: O06745, O09171, O35490, Q32LQ4, Q5I597, Q5M8Z0, Q5RF32, Q5RFG2, Q5XGM3, Q68FT5, Q91WS4, Q93088, Q95332, Q9H2M3, O33259, Q49775, Q55786

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NfKb-p65/p50	“down-regulates quantity by repression”	BHMT	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

899 predictions. Top by Δscore:

Variant	Effect	Δscore
5:79111915:GAAG:G	donor_gain	1.0000
5:79111917:AGGT:A	donor_loss	1.0000
5:79111918:GGT:G	donor_loss	1.0000
5:79111919:G:C	donor_loss	1.0000
5:79111919:G:GG	donor_gain	1.0000
5:79119249:A:AG	acceptor_gain	1.0000
5:79119257:A:AG	acceptor_gain	1.0000
5:79119257:A:G	acceptor_loss	1.0000
5:79119258:G:GA	acceptor_gain	1.0000
5:79119258:GTTC:G	acceptor_gain	1.0000
5:79119378:G:GG	donor_gain	1.0000
5:79120347:TA:T	acceptor_loss	1.0000
5:79120348:AGG:A	acceptor_gain	1.0000
5:79120349:GGG:G	acceptor_gain	1.0000
5:79120537:CAGAG:C	donor_loss	1.0000
5:79120538:AGAG:A	donor_loss	1.0000
5:79120539:GAG:G	donor_gain	1.0000
5:79120539:GAGGT:G	donor_loss	1.0000
5:79120540:AGG:A	donor_loss	1.0000
5:79120541:GGTAA:G	donor_loss	1.0000
5:79120542:GTA:G	donor_loss	1.0000
5:79120543:T:A	donor_loss	1.0000
5:79120564:A:G	donor_gain	1.0000
5:79126044:A:AG	acceptor_gain	1.0000
5:79126045:G:GG	acceptor_gain	1.0000
5:79126045:GGA:G	acceptor_gain	1.0000
5:79111914:AGAAG:A	donor_gain	0.9900
5:79111915:GAAGG:G	donor_gain	0.9900
5:79111916:AAG:A	donor_gain	0.9900
5:79111917:AG:A	donor_gain	0.9900

AlphaMissense

2645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:79126069:T:C	C217R	1.000
5:79115863:T:A	W44R	0.999
5:79115863:T:C	W44R	0.999
5:79119318:T:C	F76L	0.999
5:79119320:C:A	F76L	0.999
5:79119320:C:G	F76L	0.999
5:79121298:C:G	C186W	0.999
5:79126068:C:A	N216K	0.999
5:79126068:C:G	N216K	0.999
5:79126069:T:A	C217S	0.999
5:79126070:G:A	C217Y	0.999
5:79126070:G:C	C217S	0.999
5:79126070:G:T	C217F	0.999
5:79126071:C:G	C217W	0.999
5:79126198:G:A	G260R	0.999
5:79126198:G:C	G260R	0.999
5:79126199:G:A	G260E	0.999
5:79126201:T:C	F261L	0.999
5:79126203:C:A	F261L	0.999
5:79126203:C:G	F261L	0.999
5:79126219:T:C	F267L	0.999
5:79126221:C:A	F267L	0.999
5:79126221:C:G	F267L	0.999
5:79127839:G:A	G298E	0.999
5:79127841:T:C	C299R	0.999
5:79127842:G:A	C299Y	0.999
5:79127844:T:C	C300R	0.999
5:79127845:G:A	C300Y	0.999
5:79127848:G:A	G301E	0.999
5:79127970:T:A	W342R	0.999

dbSNP variants (sampled 300 via entrez): RS1000192019 (5:79113474 G>A), RS1000201978 (5:79113794 T>A), RS1000441319 (5:79120175 T>C), RS1000492775 (5:79126563 A>G), RS1000875860 (5:79125364 G>A,C), RS1001077325 (5:79118567 T>C), RS1001204657 (5:79112145 C>T), RS1001487749 (5:79118829 C>G,T), RS1001538016 (5:79118738 G>A), RS1001551449 (5:79113767 C>G), RS1001611606 (5:79118585 T>C), RS1001689357 (5:79131915 G>A), RS1001756994 (5:79125054 G>C), RS1001824367 (5:79131599 G>A), RS1001854243 (5:79112518 G>A)

Disease associations

OMIM: gene MIM:602888 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001852_5	Metabolite levels	2.000000e-09
GCST002039_10	Blood trace element (Se levels)	8.000000e-12
GCST002039_2	Blood trace element (Se levels)	9.000000e-28
GCST002670_10	Blood and toenail selenium levels	8.000000e-20
GCST002670_2	Blood and toenail selenium levels	6.000000e-11
GCST002670_9	Blood and toenail selenium levels	1.000000e-36
GCST002671_16	Toenail selenium levels	5.000000e-06
GCST002671_6	Toenail selenium levels	2.000000e-11
GCST003358_1	Betaine levels in individuals undergoing cardiac evaluation	7.000000e-13
GCST009391_145	Metabolite levels	7.000000e-07
GCST012020_109	Serum metabolite levels	7.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0007787	plasma betaine measurement
EFO:0010476	dimethylglycine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3391661 (PROTEIN FAMILY), CHEMBL4328 (SINGLE PROTEIN)

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

ChEMBL bioactivities

20 potent at pChembl≥5 of 21 total, top 20 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Ki	12	nM	CHEMBL211229
7.19	IC50	64	nM	CHEMBL488121
7.08	IC50	84	nM	CHEMBL443372
7.08	Kd	83	nM	CHEMBL488121
7.06	IC50	87	nM	CHEMBL211229
7.03	IC50	93	nM	CHEMBL211229
7.02	IC50	96	nM	CHEMBL211961
6.86	IC50	138	nM	CHEMBL211229
6.86	IC50	139	nM	CHEMBL486279
6.70	IC50	200	nM	CHEMBL208607
6.55	Kd	280	nM	CHEMBL211229
6.19	IC50	649	nM	CHEMBL448548
6.15	IC50	701	nM	CHEMBL442625
5.96	IC50	1100	nM	CHEMBL2403304
5.60	IC50	2500	nM	CHEMBL487301
5.49	IC50	3260	nM	CHEMBL448691
5.30	IC50	5000	nM	CHEMBL2403303
5.30	IC50	5000	nM	CHEMBL209229
5.24	IC50	5700	nM	CHEMBL209316
5.16	IC50	7000	nM	CHEMBL377442

PubChem BioAssay actives

20 with measured affinity, of 159 total; 15 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-(3-amino-3-carboxypropyl)sulfanylpentanoic acid	372128: Binding affinity to human recombinant BHMT expressed in Escherichia coli using variable levels of betaine substrate by Dixon plot	ki	0.0120	uM
5-[(3S)-3-amino-3-carboxypropyl]sulfanyl-3,3-dimethylpentanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	0.0640	uM
5-(3-amino-3-carboxypropyl)sulfanyl-3,3-dimethylpentanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	0.0840	uM
2-amino-4-[2-(carboxymethylsulfanyl)ethylsulfanyl]butanoic acid	266699: Inhibition of human BHMT	ic50	0.0960	uM
5-(3-amino-3-carboxypropyl)sulfanyl-3-methylpentanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	0.1390	uM
6-(3-amino-3-carboxypropyl)sulfanylhexanoic acid	266699: Inhibition of human BHMT	ic50	0.2000	uM
5-(3-amino-3-carboxypropyl)selanylpentanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	0.6490	uM
5-[(3R)-3-amino-3-carboxypropyl]sulfanyl-3,3-dimethylpentanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	0.7010	uM
[1-amino-3-(4-carboxy-3,3-dimethylbutyl)sulfanylpropyl]-hydroxy-oxophosphanium	757783: Inhibition of human recombinant BHMT using N-methyl-[14C]-betaine/D,L-homocysteine as substrate after 30 mins by scintiillation counting analysis	ic50	1.1000	uM
2-amino-4-[2-[carboxymethyl(methyl)amino]ethylsulfanyl]butanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	2.5000	uM
2-amino-4-(2-carboxyethylsulfanylmethylsulfanyl)butanoic acid	372126: Inhibition of human recombinant BHMT expressed in Escherichia coli using 2 mM betaine and 1 mM DL-homocysteine as substrate	ic50	3.2600	uM
5-(3-amino-3-carboxypropyl)sulfinylpentanoic acid	266699: Inhibition of human BHMT	ic50	5.0000	uM
[1-amino-3-(4-carboxybutylsulfanyl)propyl]-hydroxy-oxophosphanium	757783: Inhibition of human recombinant BHMT using N-methyl-[14C]-betaine/D,L-homocysteine as substrate after 30 mins by scintiillation counting analysis	ic50	5.0000	uM
2-amino-4-(4-phosphonobutylsulfanyl)butanoic acid	266699: Inhibition of human BHMT	ic50	5.7000	uM
4-(3-amino-3-carboxypropyl)sulfanylbenzoic acid	266699: Inhibition of human BHMT	ic50	7.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Cyclosporine	decreases expression	4
Benzo(a)pyrene	decreases methylation, increases methylation, decreases expression	3
bisphenol A	affects expression, decreases expression	2
Aflatoxin B1	decreases expression	2
afuresertib	decreases expression	1
2,4,6-tribromophenol	increases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
tetrabromobisphenol A	decreases expression	1
ciglitazone	affects binding, increases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression	1
Betaine	increases metabolic processing	1
Diethylhexyl Phthalate	decreases expression	1
Isoniazid	increases expression	1
Methionine	decreases reaction, increases metabolic processing	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2166488	Binding	Inhibition of recombinant human BHMT expressed in Escherichia coli BL31(DE3)	Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2. — J Med Chem

Clinical trials (associated diseases)

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