GRIN3A

Chr 9

glutamate ionotropic receptor NMDA type subunit 3A

Also known as: GluN3A, NMDAR-L, NMDAR3A, NR3A

NCBI Gene: 116443 ENSG00000198785 UniProt: Q8TCU5 OMIM: 606650

This gene encodes the GluN3A subunit of NMDA glutamate receptors, which are ion channels that regulate synaptic transmission and development in the central nervous system. Mutations cause neurodevelopmental disorders with intellectual disability, autism spectrum disorder, and seizures, inherited in an autosomal dominant pattern. The pathogenic mechanism involves haploinsufficiency, as the protein is intolerant to loss-of-function variants based on constraint metrics.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a subunit of the N-methyl-D-aspartate (NMDA) receptors, which belong to the superfamily of glutamate-regulated ion channels, and function in physiological and pathological processes in the central nervous system. This subunit shows greater than 90% identity to the corresponding subunit in rat. Studies in the knockout mouse deficient in this subunit suggest that this gene may be involved in the development of synaptic elements by modulating NMDA receptor activity. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.39

Clinical Summary— GRIN3A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.453

Z-score 4.61

OE 0.22 (0.13–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.74Z-score

OE missense 0.91 (0.85–0.98)

547 obs / 598.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.39)

0≤0.351.4

Missense OE?0.91 (0.85–0.98)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 9 / 40.7Missense obs/exp: 547 / 598.1Syn Z: -0.36

This gene — mechanism propensity

0.6259th %ile

GOF

0.6541th %ile

LOF

0.4234th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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.