NRXN3

Chr 14

neurexin 3

Also known as: C14orf60

NCBI Gene: 9369 ENSG00000021645 UniProt: Q9HDB5 OMIM: 600567

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.11

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in NRXN3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,974 rare PASS variants

Rare truncating (LoF)

1 in 2,300

112 rare PASS variants

Rare synonymous (reference)

1 in 44

952 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NRXN3. 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 56	1 in 2,600
South Asian	~43k	1 in 28	1 in 2,300
Remaining (unassigned)	~30k	1 in 42	1 in 4,200
European (Finnish)	~27k	1 in 100	1 in 2,000
Admixed American	~22k	1 in 42	1 in 740
African / African American	~21k	1 in 33	1 in 2,000
East Asian	~20k	1 in 47	≈ 1 in 4,600
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 6,300
Middle Eastern	~2,884	1 in 45	none seen

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): 19 of 20 coding exons well covered in gnomAD exomes; exon 10 marginal. Genomes: all 20.? see exons ↓