TNXB

protein-coding

tenascin XB, the group of Tenascins

Gene summary

This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

TNXB1
TNXB2

MANE transcript

NM_001365276.2

Inheritance

AR, AD

ClinVar variants

P:328U:2002B:1462

Top phenotype

Vesicoureteral reflux 8; Ehlers-Danlos syndrome, classic-like 1

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr6:32,041,153-32,115,334

External References & Databases

Ensembl (ENSG00000168477)

Transcript & Mutation Effects

hg38 • Region Span ~74.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ehlers-Danlos syndrome due to tenascin-X deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011670

Submitter: Labcorp Genetics (formerly Invitae)

Ehlers-Danlos syndrome due to tenascin-X deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011670

Submitter: Orphanet

Ehlers-Danlos syndrome due to tenascin-X deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011670

Submitter: Illumina

TNXB was first reported in relation to autosomal recessive Ehlers-Danlos syndrome due to tenascin X deficiency in 1997 (9288108: Burch et al. 1997). At least 10 unique variants, both missense and loss of function, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least seven probands in three publications (26799614: Mackenroth et al. 2015; 27297501: Chen et al. 2016; Demirdas et al. 2017). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by an animal model (11925569: Mao et al. 2002) and rescue experiments (30605228: Aktar et al. 2019). In summary, the TNXB gene is definitively associated with autosomal recessive Ehlers-Danlos syndrome due to tenascin X deficiency.

Ehlers-Danlos syndrome due to tenascin-X deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011670

Submitter: Genomics England PanelApp

Ehlers-Danlos syndrome due to tenascin-X deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011670

Submitter: PanelApp Australia

vesicoureteral reflux 8LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014422

Submitter: Labcorp Genetics (formerly Invitae)

familial vesicoureteral refluxSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017329

Submitter: Orphanet

Ehlers-Danlos syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020066

Submitter: G2P

Clinical Genomic Database (CGD)

Vesicoureteral reflux 8; Ehlers-Danlos syndrome, classic-like 1AD/AR

Manifestation: Cardiovascular; Dermatologic; Gastrointestinal; Musculoskeletal; Renal

Intervention: Cardiovascular; Gastrointestinal; Renal

Rationale: In Vesicoureteral reflux, monitoring and intervention related to renal sequelae may be beneficial in terms of helping to preserve renal function; In Ehlers-Danlos syndrome, reported features include aortic dilatation (which may not have a high risk of progression), severe diverticular intestinal disease with ruptured diverticula, pancolonic diverticulitis, and rectal prolapse, mitral valve prolapse requiring valve replacement, and obstructive airway disease, though it is not clear if these are all related to TNXB or to other genetic anomalies; Surveillance related to cardiovascular anomalies may be beneficial

Comments: Variants may also be involved in vesicoureteral reflux

Refs: 9288108; 11642233; 12180144; 12865992; 15793839; 15733269; 19921645; 19557868; 20301456; 21959861; 23284009; 23620400; 23768946

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNXB variants in ClinVar

21 Conditions Cataloged

Cardiovascular phenotypeTotal: 2966

not providedTotal: 1373

not specifiedTotal: 731

Ehlers-Danlos syndrome due to tenascin-X deficiencyTotal: 454

TNXB-related disorderTotal: 234

Vesicoureteral reflux 8Total: 207

Ehlers-Danlos syndromeTotal: 201

See casesTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001365276.2. 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			23 clinvar	1099 clinvar	17 clinvar	1139
missense	2 clinvar	5 clinvar	1961 clinvar	342 clinvar	3 clinvar	2313
nonsense	91 clinvar	33 clinvar	2 clinvar			126
start loss			1 clinvar			1
frameshift	109 clinvar	67 clinvar	5 clinvar			181
splice donor/acceptor (+/-2bp)		21 clinvar	10 clinvar		1 clinvar	32
Total	202	126	2002	1441	21	3792

Highest pathogenic variant AF is 0.00006370509

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001365276.2	RefSeq	NP_001352205.1	43	MANE Select
ENST00000644971.2	Ensembl	ENSP00000496448.1	43	MANE Select
NM_001428335.1	RefSeq	NP_001415264.1	44	Standard
NM_019105.8	RefSeq	NP_061978.6	43	Standard

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
actin cytoskeleton organization
collagen fibril organization
collagen metabolic process
elastic fiber assembly

Molecular Function

integrin binding
extracellular matrix structural constituent
protein binding
heparin binding
collagen fibril binding

Cellular Component

extracellular region
extracellular space
extracellular matrix
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000451343
Coding exons: 13
Length: 74181
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125694
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0433	245	247	0.992	0.0000160	4182
Missense (PolyPhen)		158	166.01	0.95173		2892
Synonymous	0.804	95	106	0.900	0.00000774	1359
Loss of Function	2.94	7	21.8	0.321	0.00000110	324

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000069	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Appears to mediate interactions between cells and the extracellular matrix. Substrate-adhesion molecule that appears to inhibit cell migration. Accelerates collagen fibril formation. May play a role in supporting the growth of epithelial tumors. {ECO:0000269|PubMed:17033827}.;
Disease: DISEASE: Ehlers-Danlos syndrome, classic-like (EDSCLL) [MIM:606408]: A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSCLL patients lack atrophic scars, a major diagnostic criteria for classic Ehlers-Danlos syndrome. Delayed wound healing is only present in a subset of patients. EDSCLL inheritance is autosomal recessive. {ECO:0000269|PubMed:11642233, ECO:0000269|PubMed:15733269, ECO:0000269|PubMed:23768946}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vesicoureteral reflux 8 (VUR8) [MIM:615963]: A disease belonging to the group of congenital anomalies of the kidney and urinary tract. It is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys, and is a risk factor for urinary tract infections. Primary disease results from a developmental defect of the ureterovesical junction. In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy. Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, renal insufficiency and end-stage renal disease. {ECO:0000269|PubMed:23620400}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.161

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High