TNR

Chr 1AR

tenascin R

Also known as: NEDSTO, TN-R

NCBI Gene: 7143 ENSG00000116147 UniProt: Q92752 OMIM: 601995

The protein is a neural extracellular matrix glycoprotein that regulates neurite outgrowth, neural cell adhesion, and sodium channel clustering at nodes of Ranvier within the central nervous system. Biallelic mutations cause a neurodevelopmental disorder with nonprogressive spasticity and transient opisthotonus, inherited in an autosomal recessive pattern. The gene shows significant constraint against loss-of-function variants (LOEUF 0.34), suggesting intolerance to protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The encoded protein is restricted to the central nervous system. The protein may play a role in neurite outgrowth, neural cell adhesion and modulation of sodium channel function. It is a constituent of perineuronal nets. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.341 OMIM phenotype

Clinical Summary— TNR

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.52) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.524

Z-score 6.14

OE 0.22 (0.15–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.60Z-score

OE missense 0.84 (0.79–0.90)

685 obs / 813.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.15–0.34)

0≤0.351.4

Missense OE?0.84 (0.79–0.90)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 16 / 72.4Missense obs/exp: 685 / 813.0Syn Z: -0.51

This gene — mechanism propensity

0.6358th %ile

GOF

0.5856th %ile

LOF

0.4529th %ile

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

DNprediction above median

LOFLOEUF 0.34

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.