MTHFS

Chr 15AR

methenyltetrahydrofolate synthetase

Also known as: HsT19268, NEDMEHM

NCBI Gene: 10588 ENSG00000136371 UniProt: P49914 OMIM: 604197

The protein catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate and helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for purine, thymidine and amino acid biosynthesis. Mutations cause autosomal recessive neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination. The gene shows tolerance to loss-of-function variants (LOEUF 1.548), suggesting the pathogenic variants may have other effects on protein function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.551 OMIM phenotype

Clinical Summary— MTHFS

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.55LOEUF

pLI 0.000

Z-score 0.50

OE 0.80 (0.44–1.55)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.55Z-score

OE missense 0.85 (0.72–1.01)

97 obs / 113.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.80 (0.44–1.55)

0≤0.351.4

Missense OE?0.85 (0.72–1.01)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 6 / 7.5Missense obs/exp: 97 / 113.6Syn Z: -0.44

This gene — mechanism propensity

0.6648th %ile

GOF

0.5465th %ile

LOF

0.2581th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.