TNR

protein-coding

tenascin R, the group of Tenascins

Gene summary

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]

MANE transcript

NM_003285.3

Inheritance

ClinVar variants

P:14U:216B:56

Top phenotype

neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr1:175,315,194-175,743,595

External References & Databases

Ensembl (ENSG00000116147)

Transcript & Mutation Effects

hg38 • Region Span ~428.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonusSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859212

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonusDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0859212

Submitter: ClinGen

*TNR* was first reported in relation to autosomal recessive neurodevelopmental disorder, non-progressive with spasticity and transient opisthotonus (NEDSTO) in 2012 (Dufresne et al., PMID: 22730557). Individuals with variants in *TNR* can present with features such as gross motor delay (specifically in walking), axial hypotonia, peripheral spasticity, opisthotonus, and varying degrees of intellectual disability. Other phenotypes can include speech delay and brain myelination anomalies. Ten variants (missense, frameshift, nonsense, large deletion) that have been reported in 16 probands in 3 publications (PMIDs: 22730557, 28334938, 32099069) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function (PMID: 22730557). This gene-disease relationship is also supported by experimental evidence such as a mouse model and expression-level evidence (PMIDs: 8626505, 12882316, 15034584). The mouse model shows that TNR-deficient mice have atypical behavior, structural brain anomalies, and impaired learning/memory. Expression-level data from healthy human tissue shows that the gene is expressed specifically in the brain. In summary, there is definitive evidence supporting the relationship between *TNR* and autosomal recessive NEDSTO. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on January 2, 2025 (SOP Version 11).

neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonusSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859212

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNR variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 199

not providedTotal: 68

Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonusTotal: 26

Non-progressive neurodevelopmental disorder with spasticity and transient opisthotonusTotal: 8

Parkinson diseaseTotal: 5

TNR-related disorderTotal: 4

not specifiedTotal: 2

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003285.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	31 clinvar	7 clinvar	39
missense	2 clinvar	2 clinvar	213 clinvar	15 clinvar	3 clinvar	235
nonsense	3 clinvar	1 clinvar	1 clinvar			5
start loss						0
frameshift	4 clinvar	1 clinvar				5
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	9	5	216	46	10	286

Highest pathogenic variant AF is 0.000027259435

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003285.3	RefSeq	NP_003276.3	21	MANE Select
ENST00000367674.7	Ensembl	ENSP00000356646.1	21	MANE Select
NM_001328635.2	RefSeq	NP_001315564.1	20	Standard
ENST00000422274.2	Ensembl	ENSP00000403413.2	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tnr	Danio rerio	Structure: optic tract Quality: branchiness abnormal

Gene / Model

Organism

Observed Phenotype

tnr

Danio rerio

Structure: optic tract

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
MicroRNAs in cancer - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)

Biological Process

cell adhesion
neuron cell-cell adhesion
axon guidance
associative learning
telencephalon cell migration

Cellular Component

extracellular region
cell surface
membrane raft
perineuronal net
Schaffer collateral - CA1 synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367674
Coding exons: 21
Length: 428577
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.60	685	813	0.843	0.0000480	8851
Missense (PolyPhen)		253	353.43	0.71585		3767
Synonymous	-0.508	341	329	1.04	0.0000214	2717
Loss of Function	6.14	16	72.4	0.221	0.00000436	700

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00065	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components. These interactions can influence cellular behavior by either evoking a stable adhesion and differentiation, or repulsion and inhibition of neurite growth. Binding to cell surface gangliosides inhibits RGD-dependent integrin-mediated cell adhesion and results in an inhibition of PTK2/FAK1 (FAK) phosphorylation and cell detachment. Binding to membrane surface sulfatides results in a oligodendrocyte adhesion and differentiation. Interaction with CNTN1 induces a repulsion of neurons and an inhibition of neurite outgrowth. Interacts with SCN2B may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier. TNR-linked chondroitin sulfate glycosaminoglycans are involved in the interaction with FN1 and mediate inhibition of cell adhesion and neurite outgrowth. The highly regulated addition of sulfated carbohydrate structure may modulate the adhesive properties of TNR over the course of development and during synapse maintenance (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.373

Intolerance Scores

LoFtool: 0.502
RVIS EVS: -0.54
RVIS percentile EVS: 20.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.832

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium