MTR

5-methyltetrahydrofolate-homocysteine methyltransferase, the group of Homocysteine methyltransferases|Methyltransferase families

Basic information

Region (hg38): 1:236795260-236921278

Links

ENSG00000116984 ∙ NCBI:4548 ∙ OMIM:156570 ∙ HGNC:7468 ∙ Uniprot:Q99707 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylcobalamin deficiency type cblG (Definitive), mode of inheritance: AR
• methylcobalamin deficiency type cblG (Supportive), mode of inheritance: AR
• methylcobalamin deficiency type cblG (Strong), mode of inheritance: AR
• methylcobalamin deficiency type cblG (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Homocystinuria-megaloblastic anemia, cblG complementation type	AR	Biochemical	Medical treatment may be beneficial (while hydroxycobalamin may not be as effective as in other MMA types, other treatments, such as betaine, methylfolate, and even methionine supplements may be attempted)	Biochemical; Cardiovascular; Hematologic; Neurologic; Renal	2897628; 2203337; 8968736; 8968737; 12068375; 20301503; 22108709

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MTR gene.

• Methylcobalamin deficiency type cblG (46 variants)
• not provided (6 variants)
• Disorders of Intracellular Cobalamin Metabolism (1 variants)
• Epilepsy;Intellectual disability, profound (1 variants)
• MTR-related disorder (1 variants)
• Decreased methionine synthase activity;Homocystinuria (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	287	8	299
missense	1	5	214	9	5	234
nonsense	14	1				15
start loss		1				1
frameshift	27	4				31
inframe indel			1			1
splice donor/acceptor (+/-2bp)	4	20	2	1		27
splice region		1	20	70	8	99
non coding	2	1	116	276	147	542
Total	48	32	337	573	160

Highest pathogenic variant AF is 0.0000854

Variants in MTR

This is a list of pathogenic ClinVar variants found in the MTR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-236795291-C-A		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
1-236795325-C-T		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
1-236795348-C-G		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 12, 2018)
1-236795360-C-T		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Apr 27, 2017)
1-236795376-T-G		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 12, 2018)
1-236795383-C-G		Disorders of Intracellular Cobalamin Metabolism	Likely benign (May 19, 2021)
1-236795395-G-A		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 12, 2018)
1-236795455-C-T		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
1-236795503-C-G		Disorders of Intracellular Cobalamin Metabolism	Benign/Likely benign (Jun 29, 2018)
1-236795506-C-G		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
1-236795531-G-A		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 12, 2018)
1-236795531-G-T		Disorders of Intracellular Cobalamin Metabolism	Likely benign (Jan 12, 2018)
1-236795553-C-T		Disorders of Intracellular Cobalamin Metabolism	Benign/Likely benign (Feb 01, 2023)
1-236795571-G-A		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jun 14, 2016)
1-236795593-C-T		Disorders of Intracellular Cobalamin Metabolism	Benign/Likely benign (May 13, 2021)
1-236795596-G-C		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
1-236795608-C-A		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Jan 13, 2018)
1-236795637-C-T		Disorders of Intracellular Cobalamin Metabolism	Benign (Nov 03, 2019)
1-236795685-AAGG-A		not specified	Likely benign (Feb 11, 2016)
1-236795698-G-C		Disorders of Intracellular Cobalamin Metabolism	Uncertain significance (Dec 16, 2022)
1-236795703-CAT-C			Likely pathogenic (Oct 11, 2017)
1-236795709-A-G		Methylcobalamin deficiency type cblG	Likely benign (Dec 13, 2022)
1-236795711-CCG-C		Methylcobalamin deficiency type cblG	Pathogenic (Dec 04, 2023)
1-236795712-C-T		Methylcobalamin deficiency type cblG	Likely benign (Jul 19, 2023)
1-236795716-C-A		Methylcobalamin deficiency type cblG • Inborn genetic diseases	Uncertain significance (Dec 06, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTR	protein_coding	protein_coding	ENST00000366577	33	108672

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.43e-12	1.00	125655	0	93	125748	0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.04	527	677	0.779	0.0000371	8317
Missense in Polyphen		171	297.93	0.57395		3623
Synonymous	-0.582	259	247	1.05	0.0000145	2384
Loss of Function	4.05	31	66.7	0.465	0.00000350	852

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000536	0.000535
Ashkenazi Jewish	0.000611	0.000595
East Asian	0.000544	0.000544
Finnish	0.000188	0.000185
European (Non-Finnish)	0.000380	0.000378
Middle Eastern	0.000544	0.000544
South Asian	0.000409	0.000392
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the transfer of a methyl group from methyl- cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity). {ECO:0000250}.
• Disease: DISEASE: Homocystinuria-megaloblastic anemia, cblG complementation type (HMAG) [MIM:250940]: An autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. It causes delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia. {ECO:0000269|PubMed:8968736, ECO:0000269|PubMed:8968737}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:12375236}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;One carbon pool by folate - Homo sapiens (human);Cysteine and methionine metabolism - Homo sapiens (human);Selenocompound metabolism - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;S-Adenosylhomocysteine (SAH) Hydrolase Deficiency;Methionine Metabolism;Methionine Adenosyltransferase Deficiency;Glycine N-methyltransferase Deficiency;Hypermethioninemia;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Betaine Metabolism;Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type;sarcosine oncometabolite pathway ;Cystathionine Beta-Synthase Deficiency;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate-Alcohol and Cancer Pathway Hypotheses;Folate Metabolism;Trans-sulfuration pathway;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;Methionine De Novo and Salvage Pathway;One carbon metabolism and related pathways;Ethanol effects on histone modifications;Methylation;Phase II - Conjugation of compounds;Folate metabolism;Metabolism of amino acids and derivatives;Biological oxidations;Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;folate transformations I;Methionine Cysteine metabolism;methionine salvage;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Sulfur amino acid metabolism (Consensus)

Recessive Scores

• pRec: 0.687

Intolerance Scores

• loftool: 0.507
• rvis_EVS: 0.25
• rvis_percentile_EVS: 69.7

Haploinsufficiency Scores

• pHI: 0.691
• hipred: Y
• hipred_score: 0.736
• ghis: 0.529

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mtr
• Phenotype: homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: nervous system development;methionine biosynthetic process;cobalamin metabolic process;axon regeneration;methylation;pteridine-containing compound metabolic process;response to axon injury;cellular response to nitric oxide
• Cellular component: cytosol
• Molecular function: protein binding;zinc ion binding;methionine synthase activity;cobalamin binding