MTHFD2

methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase

Basic information

Region (hg38): 2:74186171-74217565

Links

ENSG00000065911 ∙ NCBI:10797 ∙ OMIM:604887 ∙ HGNC:7434 ∙ Uniprot:P13995 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MTHFD2 gene.

• Inborn genetic diseases (10 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTHFD2 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				1		1
missense			9	1		10
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	9	2	0

Variants in MTHFD2

This is a list of pathogenic ClinVar variants found in the MTHFD2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-74198696-C-A		not specified	Uncertain significance (Jul 30, 2023)
2-74198696-C-T		not specified	Uncertain significance (Sep 26, 2023)
2-74198704-C-G		not specified	Uncertain significance (Nov 19, 2022)
2-74198715-T-C		not specified	Likely benign (Mar 05, 2024)
2-74198717-C-T		not specified	Uncertain significance (Jan 29, 2024)
2-74205875-C-T		not specified	Uncertain significance (Jan 16, 2024)
2-74207723-T-G		not specified	Uncertain significance (Oct 17, 2023)
2-74207745-G-A		not specified	Uncertain significance (Aug 10, 2021)
2-74207787-G-A		not specified	Uncertain significance (Jan 26, 2022)
2-74210031-G-A		not specified	Uncertain significance (Jan 17, 2023)
2-74210033-G-A			Likely benign (Jul 01, 2022)
2-74211259-C-A		not specified	Uncertain significance (Sep 19, 2023)
2-74211259-C-T		not specified	Uncertain significance (May 27, 2022)
2-74211279-A-G		not specified	Likely benign (Jun 03, 2022)
2-74211819-A-G		not specified	Uncertain significance (Dec 01, 2022)
2-74214183-C-A		not specified	Uncertain significance (Dec 15, 2022)
2-74214228-G-A		not specified	Uncertain significance (Sep 12, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTHFD2	protein_coding	protein_coding	ENST00000394053	8	19004

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00240	0.983	124831	0	20	124851	0.0000801

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.481	172	191	0.902	0.00000921	2250
Missense in Polyphen		57	72.089	0.79069		946
Synonymous	-0.384	75	70.9	1.06	0.00000359	719
Loss of Function	2.14	7	16.3	0.429	9.42e-7	182

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000240	0.000240
Ashkenazi Jewish	0.00	0.00
East Asian	0.000167	0.000166
Finnish	0.000232	0.000232
European (Non-Finnish)	0.0000266	0.0000265
Middle Eastern	0.000167	0.000166
South Asian	0.0000655	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency. {ECO:0000269|PubMed:16100107}.
• Pathway: One carbon pool by folate - Homo sapiens (human);Folate malabsorption, hereditary;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Methotrexate Action Pathway;Folate Metabolism;Folate Metabolism;miR-targeted genes in epithelium - TarBase;miR-targeted genes in leukocytes - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;Nucleotide Metabolism;Folate metabolism;Metabolism;folate transformations I;Metabolism of folate and pterines;histidine degradation;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Vitamin B9 (folate) metabolism;tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate (Consensus)

Recessive Scores

• pRec: 0.255

Intolerance Scores

• loftool: 0.447
• rvis_EVS: -0.23
• rvis_percentile_EVS: 36.86

Haploinsufficiency Scores

• pHI: 0.559
• hipred: Y
• hipred_score: 0.655
• ghis: 0.592

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.979

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mthfd2
• Phenotype: liver/biliary system phenotype; embryo 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); growth/size/body region phenotype

Gene ontology

• Biological process: tetrahydrofolate interconversion;tetrahydrofolate metabolic process;folic acid metabolic process;oxidation-reduction process
• Cellular component: extracellular space;mitochondrion;mitochondrial matrix
• Molecular function: magnesium ion binding;methenyltetrahydrofolate cyclohydrolase activity;methylenetetrahydrofolate dehydrogenase (NAD+) activity;methylenetetrahydrofolate dehydrogenase (NADP+) activity;phosphate ion binding