GNMT

protein-coding

glycine N-methyltransferase, the group of 7BS small molecule methyltransferases

Gene summary

The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

MANE transcript

NM_018960.6

Inheritance

ClinVar variants

P:2U:82B:28

Top phenotype

Glycine N-methyltransferase deficiency

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr6:42,960,754-42,963,880

External References & Databases

Ensembl (ENSG00000124713)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycine N-methyltransferase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011698

Submitter: ClinGen

The relationship between GNMT and Glycine N-methyltransferase Deficiency (AR) was evaluated using the ClinGen Clinical Validity Framework as of 03/29/19. Variants in GNMT were first reported in humans with this disease as early as 2001 (Mudd et al., PMID: 11596649). At least four variants, mostly missense, have been reported in humans in three publications (Mudd et al., 2001; PMID: 11596649; Barić et al., 2016; PMID: 27207470; Augoustides-Savvopoulou et al., 2003; PMID: 14739680). Patients with GNMT deficiency have elevated serum transaminases without other serious clinical symptoms. Evidence supporting this gene-disease relationship includes case-level data and experimental data, including animal models and expression studies. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Aminoacidopathy Working Group on 05/10/19 (SOP Version 6). It was reevaluated on 10/14/2022 and 09/23/2025 with no new evidence found. As a result of this reevaluation, the classification remained Limited.

glycine N-methyltransferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011698

Submitter: Labcorp Genetics (formerly Invitae)

glycine N-methyltransferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011698

Submitter: PanelApp Australia

glycine N-methyltransferase deficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011698

Submitter: Labcorp Genetics (formerly Invitae)

glycine N-methyltransferase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011698

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Glycine N-methyltransferase deficiencyAR

Manifestation: Biochemical; Gastrointestinal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11596649; 11810299

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNMT variants in ClinVar

4 Conditions Cataloged

not providedTotal: 100

not specifiedTotal: 45

Glycine N-methyltransferase deficiencyTotal: 5

GNMT-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018960.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	22 clinvar	2 clinvar	25
missense	2 clinvar		78 clinvar	3 clinvar	1 clinvar	84
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	0	82	25	3	112

Highest pathogenic variant AF is 0.0000035422756

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018960.6	RefSeq	NP_061833.1	6	MANE Select
ENST00000372808.4	Ensembl	ENSP00000361894.3	6	MANE Select
NM_001318865.2	RefSeq	NP_001305794.1	6	Standard
ENST00000858684.1	Ensembl	ENSP00000528743.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycine, serine and threonine metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia
Glycine and Serine Metabolism
sarcosine oncometabolite pathway

Biological Process

glycogen metabolic process
regulation of gluconeogenesis
cellular protein modification process
methionine metabolic process
one-carbon metabolic process

Molecular Function

protein binding
folic acid binding
glycine binding
glycine N-methyltransferase activity
identical protein binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372808
Coding exons: 6
Length: 3123
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.354	159	172	0.924	0.0000101	1904
Missense (PolyPhen)		51	58.938	0.86531		658
Synonymous	1.38	60	75.2	0.798	0.00000485	590
Loss of Function	1.70	6	12.5	0.482	5.38e-7	148

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the methylation of glycine by using S- adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy). Possible crucial role in the regulation of tissue concentration of AdoMet and of metabolism of methionine. {ECO:0000269|PubMed:15340920, ECO:0000269|PubMed:17660255}.;

Recessive Scores

pRec: 0.318

Intolerance Scores

LoFtool: 0.379
RVIS EVS: 0.06
RVIS percentile EVS: 58.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.974

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium