SHMT1

Chr 17

serine hydroxymethyltransferase 1

Also known as: CSHMT, SHMT, hcSHMT

NCBI Gene: 6470 ENSG00000176974 UniProt: P34896 OMIM: 182144

The cytosolic serine hydroxymethyltransferase enzyme catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate, providing one-carbon units essential for methionine, purine, and pyrimidine synthesis, and also functions in carnitine biosynthesis and as a nuclear scaffold protein for DNA replication complexes. Mutations cause autosomal recessive neurodevelopmental disorder with seizures and brain atrophy, typically presenting in infancy with developmental delays and neurological deterioration. This gene is extremely intolerant to loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the cytosolic form of serine hydroxymethyltransferase, a pyridoxal phosphate-containing enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. This reaction provides one-carbon units for synthesis of methionine, thymidylate, and purines in the cytoplasm. This gene is located within the Smith-Magenis syndrome region on chromosome 17. A pseudogene of this gene is located on the short arm of chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.36

Clinical Summary— SHMT1

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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?

1.36LOEUF

pLI 0.000

Z-score 0.20

OE 0.95 (0.68–1.36)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.35Z-score

OE missense 0.94 (0.85–1.04)

259 obs / 275.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.95 (0.68–1.36)

0≤0.351.4

Missense OE?0.94 (0.85–1.04)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 22 / 23.1Missense obs/exp: 259 / 275.5Syn Z: -0.66

This gene — mechanism propensity

0.6552th %ile

GOF

0.5072th %ile

LOF

0.4234th %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.