TCIRG1

protein-coding

T cell immune regulator 1, ATPase H+ transporting V0 subunit a3, the group of V-type ATPase subunits|MicroRNA protein coding host genes

Gene summary

This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]

MANE transcript

NM_006019.4

Inheritance

AR, AD

ClinVar variants

P:285U:563B:519

Top phenotype

Osteopetrosis, autosomal recessive 1

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr11:68,039,025-68,050,895

External References & Databases

Ensembl (ENSG00000110719)

Transcript & Mutation Effects

hg38 • Region Span ~11.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019026

Submitter: Myriad Women's Health

dysosteosclerosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009138

Submitter: ClinGen

TCIRG1 was first reported in relation to Autosomal Recessive Dysosteosclerosis in 2019 (Howaldt et al., PMID: 30537558). Dysosteosclerosis is a rare genetic primary bone dysplasia disease characterized by sandwich vertebrae, progressive osteosclerosis and platyspondyly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in phenotypic spectrum of the disease assertions with this gene. Therefore, the following disease entities have been split into multiple disease entities: Autosomal Recessive Osteopetrosis 1 (MONDO:0009815) and Dysosteosclerosis (ORPHA: 1782). The split curation for autosomal recessive Osteopetrosis 1 (OMIM:259700) has been curated separately. This curation is for autosomal recessive Dysosteosclerosis. Two variants (1 frameshift, 1 splice region) that have been reported in a family consisting of 2 affected siblings in 1 publication (PMID: 30537558) are included in this curation. The mechanism of pathogenicity is presumed to be loss of function though more evidence is required. This gene-disease association is also supported by expression data. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 12/4/23 (SOP Version 9).

autosomal recessive osteopetrosis 6SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012679

Submitter: Orphanet

autosomal recessive osteopetrosis 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009815

Submitter: Natera

autosomal dominant severe congenital neutropeniaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008742

Submitter: Orphanet

dysosteosclerosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009138

Submitter: Orphanet

autosomal recessive osteopetrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019026

Submitter: Orphanet

autosomal recessive osteopetrosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009815

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive osteopetrosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009815

Submitter: PanelApp Australia

autosomal recessive osteopetrosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009815

Submitter: Genomics England PanelApp

autosomal recessive osteopetrosis 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009815

Submitter: ClinGen

*TCIRG1* was first reported in relation to autosomal recessive Osteopetrosis 1 in 2000 (Frattini et al., PMID:10888887). Osteopetrosis is caused by subnormal osteoclast function that typically manifests in the first few months of life. It is characterized by: abnormally dense bone, macrocephaly and frontal bossing, tooth defects, feeding difficulties, visual and hearing loss, bone marrow insufficiency, severe anemia, and hepatosplenomegaly. At the time of this curation, there were no other single-gene disorders associated with this gene. This curation is based on this disease entity only. 24 variants (missense, splice site, frameshift, nonsense) that have been reported in 12 probands in three publications (PMIDs: 11532986, 10888887, 34545712) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by animal models, expression studies, and functional alteration studies (PMIDs:10888887,19448635,11532986, 10709991). In summary, *TCIRG1* is definitively associated with autosomal recessive Osteopetrosis 1. 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 Skeletal Disorders GCEP on the meeting date 03/01/23 (SOP Version 9).

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal recessive 1AR

Manifestation: Audiologic/Otolaryngologic; Dental; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Hematologic; Musculoskeletal

Rationale: Although the disorder may be frequently recognizable, medical treatments (eg, calcitriol, interferon gamma-1b) as well as surgical interventions may be beneficial; Early and aggressive treatment of infectious and hematologic manifestations, as well as neonatal hypocalcemia, which can result in tetanic seizures, may be beneficial; Awareness of multi-organ system complications may allow surveillance and prompt interventions; BMT/HSCT has been described

Comments: Milder forms of disease, possibly due to heterozygous variants have been described

Refs: 13532685; 4170880; 6986555; 6546410; 2877234; 1320672; 8291528; 7996361; 7753137; 10888887; 10942435; 12566520; 20870624; 20424301; 21042819; 23329773; 23412864

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCIRG1 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 1498

Autosomal recessive osteopetrosis 1Total: 480

Inborn genetic diseasesTotal: 167

TCIRG1-related disorderTotal: 54

not specifiedTotal: 22

OsteopetrosisTotal: 13

Decreased total neutrophil countTotal: 4

Neutropenia, severe congenital, 1, autosomal dominantTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006019.4. 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	22 clinvar	485 clinvar		508
missense	3 clinvar	19 clinvar	530 clinvar	30 clinvar	3 clinvar	585
nonsense	27 clinvar	30 clinvar	2 clinvar			59
start loss						0
frameshift	54 clinvar	83 clinvar	4 clinvar			141
splice donor/acceptor (+/-2bp)	17 clinvar	51 clinvar	5 clinvar	1 clinvar		74
Total	101	184	563	516	3	1367

Highest pathogenic variant AF is 0.00029316862

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 77 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006019.4	RefSeq	NP_006010.2	19	MANE Select
ENST00000265686.8	Ensembl	ENSP00000265686.3	19	MANE Select
NM_001351059.2	RefSeq	NP_001337988.1	12	Standard
NM_001440552.1	RefSeq	NP_001427481.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)

Biological Process

cellular defense response
vacuolar acidification
protein catabolic process in the vacuole
positive regulation of cell population proliferation
insulin receptor signaling pathway

Molecular Function

transporter activity
proton-transporting ATPase activity, rotational mechanism
ATPase binding

Cellular Component

vacuolar proton-transporting V-type ATPase, V0 domain
lysosomal membrane
plasma membrane
integral component of plasma membrane
endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265686
Coding exons: 19
Length: 11880
Individuals with no LoFs: 125630
Homozygous LoFs: 0
Heterozygous LoFs: 116
Defined: 125746
p: 0.000461

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.627	489	530	0.923	0.0000379	5307
Missense (PolyPhen)		189	223.42	0.84596		2400
Synonymous	-0.468	247	238	1.04	0.0000177	1752
Loss of Function	2.26	27	43.0	0.628	0.00000242	409

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00045	0.00042	rare
European (Non-Finnish)	0.00058	0.00057	rare
South Asian	0.00046	0.00046	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the proton channel of V-ATPases (By similarity). Seems to be directly involved in T-cell activation. {ECO:0000250}.;

Recessive Scores

pRec: 0.386

Intolerance Scores

LoFtool: 0.0490
RVIS EVS: -1.12
RVIS percentile EVS: 6.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.396

Gene Damage Prediction

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