MAT1A

Chr 10ADAR

methionine adenosyltransferase 1A

Also known as: MAT, MATA1, SAMS, SAMS1

NCBI Gene: 4143 ENSG00000151224 UniProt: Q00266 OMIM: 610550

This gene encodes methionine adenosyltransferase, which catalyzes the formation of S-adenosylmethionine from methionine and ATP, providing methyl groups for most biological methylations. Mutations cause methionine adenosyltransferase deficiency, presenting as persistent hypermethioninemia with both autosomal dominant and autosomal recessive inheritance patterns described. The gene shows low constraint against loss-of-function variants (pLI 0.0008, LOEUF 0.81), consistent with the observation that some individuals with deficiency may be asymptomatic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene catalyzes a two-step reaction that involves the transfer of the adenosyl moiety of ATP to methionine to form S-adenosylmethionine and tripolyphosphate, which is subsequently cleaved to PPi and Pi. S-adenosylmethionine is the source of methyl groups for most biological methylations. The encoded protein is found as a homotetramer (MAT I) or a homodimer (MAT III) whereas a third form, MAT II (gamma), is encoded by the MAT2A gene. Mutations in this gene are associated with methionine adenosyltransferase deficiency. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.812 OMIM phenotypes

Clinical Summary— MAT1A

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Gene-Disease Validity (ClinGen)

methionine adenosyltransferase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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?

0.81LOEUF

pLI 0.001

Z-score 2.16

OE 0.45 (0.26–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.65Z-score

OE missense 0.70 (0.61–0.79)

166 obs / 237.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.26–0.81)

0≤0.351.4

Missense OE?0.70 (0.61–0.79)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 8 / 17.8Missense obs/exp: 166 / 237.8Syn Z: -0.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMAT1A-related methionine adenosyltransferase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.78top 25%

GOF

0.6932th %ile

LOF

0.2776th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNConfirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by 1

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

References