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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.36

LOEUF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in SHMT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

581 rare PASS variants

Rare truncating (LoF)

1 in 810

117 rare PASS variants

Rare synonymous (reference)

1 in 250

247 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SHMT1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 370
South Asian	~43k	1 in 89	1 in 510
Remaining (unassigned)	~30k	1 in 110	1 in 910
European (Finnish)	~27k	1 in 560	1 in 3,000
Admixed American	~22k	1 in 110	1 in 380
African / African American	~21k	1 in 92	1 in 550
East Asian	~20k	1 in 120	1 in 460
Ashkenazi Jewish	~13k	1 in 1,500	1 in 520
Middle Eastern	~2,884	1 in 110	≈ 1 in 710

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓