ANTXR2

protein-coding

ANTXR cell adhesion molecule 2

Gene summary

This gene encodes a receptor for anthrax toxin. The protein binds to collagen IV and laminin, suggesting that it may be involved in extracellular matrix adhesion. Mutations in this gene cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

MANE transcript

NM_058172.6

Inheritance

ClinVar variants

P:42U:70B:20

Top phenotype

Hyaline fibromatosis syndrome

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr4:79,901,146-80,125,454

External References & Databases

Ensembl (ENSG00000163297)

Transcript & Mutation Effects

hg38 • Region Span ~224.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyaline fibromatosis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009229

Submitter: ClinGen

The ANTXR2 gene is located on chromosome 4q21.21 and encodes a 55 kDa type I transmembrane protein. ANTXR2 was first reported in relation to autosomal recessive hyaline fibromatosis syndrome in 2003 (Hanks et al., PMID: 14508707; Dowling et al., PMID: 12973667). Hyaline fibromatosis syndrome (HFS) is characterized by accumulation of amorphous, unidentified hyaline material in the skin and other organs. Clinical features of HFS include progressive contractures, hyperpigmented skin over bony prominences, subcutaneous nodules, gingival thickening, and failure to thrive secondary to protein-losing enteropathy. HFS is a progressive disease and its manifestations tend to be additive over time. At least 50 variants (including missense, nonsense, frameshift, deletions, and splice variants) have been reported in the literature. Nine variants, including 5 missense variants and 4 frameshift variants that have been reported in 7 probands in four publications are included in this curation (PMID: 12973667; Deuquet et al., 2011, PMID: 21328543; Denadai et al., 2012, PMID: 22383261; Mohamed et al., 2017, PMID: 25458638). The gene-disease relationship is supported by markedly reduced protein expression in patient cells (Burgi et al., 2017, PMID: 28604699), homozygous knockout mice (PMID: 28604699), and rescue of protein expression in patient cells (PMID: 21328543; Burgi et al., 2020, PMID: 32428455). In summary, there is definitive evidence to support the relationship between ANTXR2 and autosomal recessive hyaline fibromatosis syndrome. 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 Syndromic Disorders GCEP on the meeting date 11.22.2022 (SOP Version 9.0).

juvenile hyaline fibromatosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016071

Submitter: Orphanet

infantile systemic hyalinosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016331

Submitter: Orphanet

hyaline fibromatosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009229

Submitter: Labcorp Genetics (formerly Invitae)

juvenile hyaline fibromatosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016071

Submitter: G2P

hyaline fibromatosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009229

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hyaline fibromatosis syndromeAR

Manifestation: Allergy/Immunology/Infectious; Dental; Dermatologic; Gastrointestinal; Musculoskeletal

Intervention: Allergy/Immunology/Infectious; Dermatologic; Musculoskeletal

Rationale: The condition may be clinically recognizable, but involves manifestations that require clinical care, such as fracture susceptibility, intractable diarrhea, and infection susceptibility, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 20896407; 20896998; 55105; 2434938; 2433666; 3544844; 487969; 11206353; 12214284; 11298373; 12973667; 14508707

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANTXR2 variants in ClinVar

7 Conditions Cataloged

Hyaline fibromatosis syndromeTotal: 67

not providedTotal: 58

Inborn genetic diseasesTotal: 37

not specifiedTotal: 27

ANTXR2-related disorderTotal: 12

Central core myopathyTotal: 1

Juvenile hyaline fibromatosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_058172.6. 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		1 clinvar	13 clinvar		15
missense	4 clinvar	7 clinvar	65 clinvar	6 clinvar	1 clinvar	83
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss						0
frameshift	6 clinvar	11 clinvar				17
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	3 clinvar			13
Total	15	27	70	19	1	132

Highest pathogenic variant AF is 0.00027614637

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_058172.6	RefSeq	NP_477520.2	17	MANE Select
ENST00000403729.7	Ensembl	ENSP00000385575.2	17	MANE Select
NM_001145794.2	RefSeq	NP_001139266.1	16	Standard
NM_001286780.2	RefSeq	NP_001273709.1	15	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
antxr2a	Danio rerio	Structure: anterior neural plate Quality: increased width abnormal

Gene / Model

Organism

Observed Phenotype

antxr2a

Danio rerio

Structure: anterior neural plate

Quality: increased width

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOD-like receptor signaling pathway - Homo sapiens (human)
Disease
Uptake and actions of bacterial toxins
Uptake and function of anthrax toxins
Infectious disease

Biological Process

reproductive process
toxin transport

Molecular Function

transmembrane signaling receptor activity
protein binding
metal ion binding

Cellular Component

extracellular region
endoplasmic reticulum membrane
plasma membrane
external side of plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307333
Coding exons: 16
Length: 224306
Individuals with no LoFs: 124607
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 124636
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.03	191	235	0.812	0.0000118	3083
Missense (PolyPhen)		64	93.821	0.68215		1254
Synonymous	0.606	75	82.0	0.915	0.00000407	946
Loss of Function	3.47	7	26.1	0.268	0.00000124	362

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00027	0.00026	rare
Latino/Admixed American	0.000092	0.000087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000034	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Necessary for cellular interactions with laminin and the extracellular matrix. {ECO:0000269|PubMed:11683410, ECO:0000269|PubMed:12973667}.;
Disease: DISEASE: Hyaline fibromatosis syndrome (HFS) [MIM:228600]: An autosomal recessive syndrome characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Disease severity is variable. Some individuals manifest symptoms in infancy and have additional visceral or systemic involvement. Hyaline deposits in multiple organs, recurrent infections and intractable diarrhea often lead to early death. Surviving children may suffer from severely reduced mobility due to joint contractures. Other patients have later onset of a milder disorder affecting only the face and digits. {ECO:0000269|PubMed:12973667, ECO:0000269|PubMed:14508707, ECO:0000269|PubMed:15725249}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.540
RVIS EVS: 0.57
RVIS percentile EVS: 82.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.669

Gene Damage Prediction

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