STING1

protein-coding

stimulator of interferon response cGAMP interactor 1

Gene summary

This gene encodes a five transmembrane protein that functions as a major regulator of the innate immune response to viral and bacterial infections. The encoded protein is a pattern recognition receptor that detects cytosolic nucleic acids and transmits signals that activate type I interferon responses. The encoded protein has also been shown to play a role in apoptotic signaling by associating with type II major histocompatibility complex. Mutations in this gene are the cause of infantile-onset STING-associated vasculopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

Previous symbols:

TMEM173

MANE transcript

NM_198282.4

Inheritance

AD, AR

ClinVar variants

P:13U:201B:111

Top phenotype

STING-associated vasculopathy, infantile-onsent (SAVI)

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr5:139,475,533-139,482,935

External References & Databases

Ensembl (ENSG00000184584)

Transcript & Mutation Effects

hg38 • Region Span ~7.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial chilblain lupusSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018827

Submitter: Orphanet

STING-associated vasculopathy with onset in infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014405

Submitter: Orphanet

STING-associated vasculopathy with onset in infancySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014405

Submitter: Genomics England PanelApp

STING-associated vasculopathy with onset in infancySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014405

Submitter: PanelApp Australia

STING-associated vasculopathy with onset in infancySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014405

Submitter: PanelApp Australia

STING-associated vasculopathy with onset in infancySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014405

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

STING-associated vasculopathy, infantile-onsent (SAVI)AD

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Hematologic; Pulmonary

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25029335; 25401470

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STING1 variants in ClinVar

7 Conditions Cataloged

STING-associated vasculopathy with onset in infancyTotal: 347

Inborn genetic diseasesTotal: 58

not specifiedTotal: 47

not providedTotal: 46

Autoinflammatory syndromeTotal: 41

STING1-related disorderTotal: 11

TMEM173-related disordersTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198282.4. 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			7 clinvar	81 clinvar	1 clinvar	89
missense	5 clinvar	8 clinvar	171 clinvar	27 clinvar	1 clinvar	212
nonsense			6 clinvar			6
start loss			1 clinvar			1
frameshift			12 clinvar			12
splice donor/acceptor (+/-2bp)			4 clinvar	1 clinvar		5
Total	5	8	201	109	2	325

Highest pathogenic variant AF is 0.000006814969

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198282.4	RefSeq	NP_938023.1	6	MANE Select
ENST00000330794.9	Ensembl	ENSP00000331288.4	6	MANE Select
NM_001301738.2	RefSeq	NP_001288667.1	5	Standard
NM_001367258.1	RefSeq	NP_001354187.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tmem173	Danio rerio	Structure: trunk Quality: shortened abnormal

Gene / Model

Organism

Observed Phenotype

tmem173

Danio rerio

Structure: trunk

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytosolic DNA-sensing pathway - Homo sapiens (human)
NOD-like receptor signaling pathway - Homo sapiens (human)
RIG-I-like receptor signaling pathway - Homo sapiens (human)
RIG-I-like Receptor Signaling
Neutrophil degranulation

Biological Process

activation of innate immune response
positive regulation of defense response to virus by host
apoptotic process
viral process
positive regulation of protein binding

Molecular Function

protein binding
transcription factor binding
protein kinase binding
ubiquitin protein ligase binding
cyclic-di-GMP binding

Cellular Component

mitochondrial outer membrane
peroxisome
endoplasmic reticulum membrane
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330794
Coding exons: 6
Length: 7402
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125746
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.64	160	230	0.695	0.0000139	2408
Missense (PolyPhen)		44	78.254	0.56227		896
Synonymous	0.00177	100	100	1.00	0.00000552	827
Loss of Function	1.83	7	14.6	0.481	6.84e-7	161

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double- stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway. Essential for the induction of IFN-beta in response to human herpes simplex virus 1 (HHV-1) infection. Exhibits 2',3' phosphodiester linkage-specific ligand recognition. Can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263). {ECO:0000269|PubMed:18724357, ECO:0000269|PubMed:18818105, ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:19776740, ECO:0000269|PubMed:21074459, ECO:0000269|PubMed:21947006, ECO:0000269|PubMed:23027953, ECO:0000269|PubMed:23258412, ECO:0000269|PubMed:23707065, ECO:0000269|PubMed:23722158, ECO:0000269|PubMed:26229117, ECO:0000269|PubMed:26300263, ECO:0000269|PubMed:26669264}.;
Disease: DISEASE: STING-associated vasculopathy, infantile-onset (SAVI) [MIM:615934]: An autoinflammatory disease characterized by early- onset systemic inflammation and cutaneous vasculopathy, resulting in severe skin lesions. Violaceous, scaling lesions of fingers, toes, nose, cheeks and ears progress to acral necrosis in most of the patients. Some patients have severe interstitial lung disease. {ECO:0000269|PubMed:25029335}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0932

Intolerance Scores

LoFtool: 0.605
RVIS EVS: 1.15
RVIS percentile EVS: 92.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.774

Gene Damage Prediction

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