NRXN3

Chr 14

neurexin 3

Also known as: C14orf60

NCBI Gene: 9369 ENSG00000021645 UniProt: Q9HDB5

NRXN3 encodes a presynaptic neuronal cell adhesion molecule that functions in trans-synaptic complexes to regulate NMDA and AMPA receptor activity at hippocampal synapses. Mutations cause neurodevelopmental disorders including autism spectrum disorder and intellectual disability with autosomal dominant inheritance. The gene is highly constrained against loss-of-function mutations, indicating that NRXN3 variants are likely to have significant clinical impact.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of a family of proteins that function in the nervous system as receptors and cell adhesion molecules. Extensive alternative splicing and the use of alternative promoters results in multiple transcript variants and protein isoforms for this gene, but the full-length nature of many of these variants has not been determined. Transcripts that initiate from an upstream promoter encode alpha isoforms, which contain epidermal growth factor-like (EGF-like) sequences and laminin G domains. Transcripts initiating from the downstream promoter encode beta isoforms, which lack EGF-like sequences. Genetic variation at this locus has been associated with a range of behavioral phenotypes, including alcohol dependence and autism spectrum disorder. [provided by RefSeq, Dec 2012]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— NRXN3

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 137 VUS of 215 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 5.90

OE 0.02 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.44Z-score

OE missense 0.62 (0.57–0.68)

409 obs / 657.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.62 (0.57–0.68)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 42.5Missense obs/exp: 409 / 657.0Syn Z: 0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNRXN3-related autismLOFAD

This gene — mechanism propensity

0.4388th %ile

GOF

0.4776th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.11

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

215 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS137

Likely Benign46

Benign13

Pathogenic

137

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	3	131	3	0	137
Likely Benign	1	6	7	32	46
Benign	0	1	6	6	13
Total	4	139	16	38	197

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap NRXN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →