MTHFS

protein-coding

methenyltetrahydrofolate synthetase

Gene summary

The protein encoded by this gene is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates involved in 1-carbon metabolism. An increased activity of the encoded protein can result in an increased folate turnover rate and folate depletion. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

MANE transcript

NM_006441.4

Inheritance

ClinVar variants

P:8U:28B:16

Top phenotype

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr15:79,833,585-79,897,379

External References & Databases

Ensembl (ENSG00000136371)

Transcript & Mutation Effects

hg38 • Region Span ~63.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelinationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032705

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelinationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032705

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelinationAR

Manifestation: Biochemical; Neurologic

Intervention: Neurologic

Rationale: 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

Refs: 30031689

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTHFS variants in ClinVar

4 Conditions Cataloged

not providedTotal: 41

not specifiedTotal: 12

MTHFS-related disorderTotal: 8

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelinationTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006441.4. 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	8 clinvar	1 clinvar	10
missense	1 clinvar	2 clinvar	26 clinvar	4 clinvar	3 clinvar	36
nonsense	2 clinvar	1 clinvar				3
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	4	4	28	12	4	52

Highest pathogenic variant AF is 0.0001400227

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006441.4	RefSeq	NP_006432.1	3	MANE Select
ENST00000258874.4	Ensembl	ENSP00000258874.4	3	MANE Select
NM_001199758.1	RefSeq	NP_001186687.1	2	Standard
ENST00000559722.2	Ensembl	ENSP00000489076.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

glutamate metabolic process
folic acid-containing compound biosynthetic process
formate metabolic process
tetrahydrofolate interconversion
tetrahydrofolate metabolic process

Molecular Function

ATP binding
folic acid binding
5-formyltetrahydrofolate cyclo-ligase activity
metal ion binding

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258874
Coding exons: 3
Length: 63795
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125748
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.553	97	114	0.854	0.00000598	1323
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.229

Intolerance Scores

LoFtool: 0.547
RVIS EVS: 0.04
RVIS percentile EVS: 56.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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