MTRR

5-methyltetrahydrofolate-homocysteine methyltransferase reductase

Basic information

Region (hg38): 5:7851186-7906025

Links

ENSG00000124275 ∙ NCBI:4552 ∙ OMIM:602568 ∙ HGNC:7473 ∙ Uniprot:Q9UBK8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

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

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Homocystinuria-megaloblastic anemia, cobalamin E type	AR	Biochemical	Treatment (eg, with hydroxycobalamin, folate, methylcobalamin) has been reported as effective	Biochemical; Hematologic; Neurologic; Renal	6700644; 2860337; 3812589; 9427140; 10444342; 15060097; 15979034; 15714522

ClinVar

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

• Methylcobalamin_deficiency_type_cblE (824 variants)
• Inborn_genetic_diseases (99 variants)
• Neural_tube_defects,_folate-sensitive (79 variants)
• not_provided (74 variants)
• Disorders_of_Intracellular_Cobalamin_Metabolism (59 variants)
• not_specified (40 variants)
• MTRR-related_disorder (14 variants)
• Congenital_myopathy (1 variants)
• Homocystinuria_without_methylmalonic_aciduria (1 variants)
• Methylcobalamin_deficiency_type_cblG (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTRR gene is commonly pathogenic or not. These statistics are base on transcript: NM_000002454.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	331	4	338
missense		5	225	19	1	250
nonsense	20	19				39
start loss	1					1
frameshift	39	29	2			70
splice donor/acceptor (+/-2bp)		32	2	1		35
Total	60	85	232	351	5

Highest pathogenic variant AF is 0.0000799307

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTRR	protein_coding	protein_coding	ENST00000264668	15	54840

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.18e-14	0.594	125636	0	112	125748	0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.665	423	386	1.10	0.0000210	4699
Missense in Polyphen		142	152.51	0.93111		1858
Synonymous	-1.38	172	150	1.14	0.00000864	1447
Loss of Function	1.64	27	37.9	0.713	0.00000207	439

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000694	0.000687
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000109	0.000109
Finnish	0.000277	0.000277
European (Non-Finnish)	0.000528	0.000528
Middle Eastern	0.000109	0.000109
South Asian	0.000621	0.000621
Other	0.00115	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the reductive regeneration of cob(I)alamin (vitamin B12) cofactor required for the maintenance of methionine synthase in a functional state. Necessary for utilization of methylgroups from the folate cycle, thereby affecting transgenerational epigenetic inheritance. Folate pathway donates methyl groups necessary for cellular methylation and affects different pathways such as DNA methylation, possibly explaining the transgenerational epigenetic inheritance effects. {ECO:0000269|PubMed:17892308}.
• Disease: DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:10444342, ECO:0000269|PubMed:12375236}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Vitamin B12 Metabolism;Folate Metabolism;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;One Carbon Metabolism;Methylation;Phase II - Conjugation of compounds;Metabolism of amino acids and derivatives;Biological oxidations;Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Sulfur amino acid metabolism (Consensus)

Recessive Scores

• pRec: 0.305

Intolerance Scores

• loftool: 0.510
• rvis_EVS: 1.43
• rvis_percentile_EVS: 95

Haploinsufficiency Scores

• pHI: 0.0348
• hipred: N
• hipred_score: 0.338
• ghis: 0.408

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.108

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mtrr
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: DNA methylation;methionine metabolic process;methionine biosynthetic process;cobalamin metabolic process;S-adenosylmethionine cycle;homocysteine catabolic process;folic acid metabolic process;homocysteine metabolic process;oxidation-reduction process;negative regulation of cystathionine beta-synthase activity
• Cellular component: cytosol
• Molecular function: NADPH-hemoprotein reductase activity;protein binding;FMN binding;oxidoreductase activity;oxidoreductase activity, oxidizing metal ions, NAD or NADP as acceptor;[methionine synthase] reductase activity;aquacobalamin reductase (NADPH) activity;flavin adenine dinucleotide binding;NADP binding;NADPH binding;FAD binding