MTHFS

methenyltetrahydrofolate synthetase

Basic information

Region (hg38): 15:79833585-79897379

Links

ENSG00000136371 ∙ NCBI:10588 ∙ OMIM:604197 ∙ HGNC:7437 ∙ Uniprot:P49914 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination	AR	Neurologic	Individuals have been described with refractory seizures and recurrent episodes of hyperthermia, which responded to lamotrigine; A combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin has been described as resulting in mild functional improvements	Biochemical; Neurologic	30031689

ClinVar

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

• Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTHFS 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				6	1	7
missense			20	3	4	27
nonsense	1	1	1			3
start loss						0
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1	2		3
non coding				2		2
Total	2	1	21	11	5

Highest pathogenic variant AF is 0.0000394

Variants in MTHFS

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

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

Position	Type	Phenotype	Significance	ClinVar
15-79845217-G-A			Uncertain significance (Mar 01, 2022)
15-79845218-T-C			Benign (Feb 03, 2025)
15-79845222-C-T			Likely benign (Jun 26, 2024)
15-79845230-C-T			Benign (Nov 03, 2024)
15-79845257-C-T			Uncertain significance (May 22, 2024)
15-79845258-G-A			Likely benign (Jun 03, 2022)
15-79845306-C-G			Likely benign (Oct 06, 2023)
15-79845338-G-A		Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination	Likely pathogenic (Apr 30, 2019)
15-79845388-C-T		Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination	Conflicting classifications of pathogenicity (Dec 22, 2023)
15-79845402-G-A		MTHFS-related disorder	Benign (Oct 10, 2024)
15-79845447-G-A			Likely benign (Apr 07, 2022)
15-79889094-T-C			Uncertain significance (Aug 03, 2022)
15-79889095-G-A			Uncertain significance (May 12, 2022)
15-79889113-C-T			Uncertain significance (Nov 05, 2024)
15-79889117-C-G			Likely benign (Oct 01, 2024)
15-79889137-G-A			Uncertain significance (Aug 04, 2023)
15-79889152-G-A			Uncertain significance (Oct 22, 2024)
15-79889156-T-A		Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination	Pathogenic (Sep 09, 2021)
15-79889179-G-A			Uncertain significance (May 16, 2022)
15-79889189-T-C			Uncertain significance (Aug 31, 2022)
15-79889221-C-T		not specified	Conflicting classifications of pathogenicity (Nov 05, 2024)
15-79889222-G-A			Uncertain significance (Jul 02, 2022)
15-79889227-C-T		not specified	Uncertain significance (Mar 03, 2025)
15-79889228-G-A			Uncertain significance (Aug 31, 2022)
15-79889252-G-A			Pathogenic (Mar 11, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTHFS	protein_coding	protein_coding	ENST00000258874	3	63795

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000258	0.556	125721	0	27	125748	0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.553	97	114	0.854	0.00000598	1323
Missense in Polyphen		37	45.36	0.8157		526
Synonymous	-0.436	47	43.3	1.08	0.00000230	389
Loss of Function	0.504	6	7.49	0.801	5.01e-7	79

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000206	0.000206
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.000109	0.000109
South Asian	0.0000980	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids. Catalyzes the irreversible conversion of 5-formyltetrahydrofolate (5-FTHF) to yield 5,10- methenyltetrahydrofolate. {ECO:0000269|PubMed:8522195}.
• Pathway: Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;One carbon pool by folate - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;Folate malabsorption, hereditary;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Methotrexate Action Pathway;Folate Metabolism;Folate Metabolism;One Carbon Metabolism;Folate metabolism;Metabolism;folate transformations I;Metabolism of folate and pterines;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;Vitamin B9 (folate) metabolism (Consensus)

Recessive Scores

• pRec: 0.229

Intolerance Scores

• loftool: 0.547
• rvis_EVS: 0.04
• rvis_percentile_EVS: 56.64

Haploinsufficiency Scores

• pHI: 0.111
• hipred: N
• hipred_score: 0.166
• ghis: 0.493

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mthfs
• 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: glutamate metabolic process;folic acid-containing compound biosynthetic process;formate metabolic process;tetrahydrofolate interconversion;tetrahydrofolate metabolic process;folic acid metabolic process;folic acid catabolic process
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix;cytosol
• Molecular function: ATP binding;folic acid binding;5-formyltetrahydrofolate cyclo-ligase activity;metal ion binding