NLGN4Y

Chr Y

neuroligin 4 Y-linked

Also known as: HNL4Y

NCBI Gene: 22829 ENSG00000165246 UniProt: Q8NFZ3

This protein functions as a postsynaptic cell adhesion molecule that interacts with neurexins to facilitate cell-cell interactions essential for functional synapse formation. Mutations cause X-linked intellectual disability and autism spectrum disorders. The gene follows X-linked inheritance and shows relatively low constraint to loss-of-function variation.

ResearchSummary from RefSeq, UniProt

This gene encodes a type I membrane protein that belongs to the family of neuroligins, which are cell adhesion molecules present at the postsynaptic side of the synapse, and may be essential for the formation of functional synapses. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Mar 2011]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.86

Clinical Summary— NLGN4Y

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.099

Z-score 1.85

OE 0.33 (0.15–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.42Z-score

OE missense 0.69 (0.60–0.81)

118 obs / 170.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.15–0.86)

0≤0.351.4

Missense OE?0.69 (0.60–0.81)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 3 / 9.0Missense obs/exp: 118 / 170.0Syn Z: -0.99

This gene — mechanism propensity

0.6939th %ile

GOF

0.6931th %ile

LOF

0.3261th %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.