TREX1

three prime repair exonuclease 1, the group of SET complex|Exonucleases

Basic information

Region (hg38): 3:48465811-48467645

Previous symbols: [ "AGS1" ]

Links

ENSG00000213689 ∙ NCBI:11277 ∙ OMIM:606609 ∙ HGNC:12269 ∙ Uniprot:Q9NSU2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Aicardi-Goutieres syndrome 1 (Definitive), mode of inheritance: AR
• Aicardi-Goutieres syndrome 1 (Strong), mode of inheritance: AD
• chilblain lupus 1 (Strong), mode of inheritance: AD
• Aicardi-Goutieres syndrome 1 (Strong), mode of inheritance: AR
• Aicardi-Goutieres syndrome 1 (Strong), mode of inheritance: AD
• Aicardi-Goutieres syndrome 1 (Strong), mode of inheritance: AR
• retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Strong), mode of inheritance: AD
• Aicardi-Goutieres syndrome (Supportive), mode of inheritance: AD
• retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Supportive), mode of inheritance: AD
• familial chilblain lupus (Supportive), mode of inheritance: AD
• Aicardi-Goutieres syndrome 1 (Strong), mode of inheritance: AR
• chilblain lupus 1 (Strong), mode of inheritance: AD
• retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Aicardi-Goutieres syndrome 1	AD/AR	Cardiovascular; Pulmonary	The condition may include pulmonary hypertension, and awareness may allow surveillance, prompt diagnosis of disease, and management of this sequelae	Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic; Pulmonary	6712192; 3731164; 3174024; 1821204; 8592332; 9371916; 10449133; 15807828; 16845398; 16960810; 17440703; 17660818; 17846997; 17660820; 20301648; 20799324; 21808053; 22356656; 22829693; 30219631

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TREX1 gene.

• Aicardi-Goutieres syndrome 1;Chilblain lupus 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (16 variants)
• Aicardi-Goutieres syndrome 1 (10 variants)
• not provided (7 variants)
• Aicardi-Goutieres syndrome 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Chilblain lupus 1 (4 variants)
• Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Aicardi-Goutieres syndrome 1;Chilblain lupus 1 (3 variants)
• Chilblain lupus 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Aicardi-Goutieres syndrome 1 (3 variants)
• Aicardi-Goutieres syndrome 1, autosomal dominant (2 variants)
• Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Chilblain lupus 1;Aicardi-Goutieres syndrome 1 (2 variants)
• Chilblain lupus 1;Aicardi-Goutieres syndrome 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (2 variants)
• Chilblain lupus (1 variants)
• Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1 variants)
• Aicardi-Goutieres syndrome 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;Chilblain lupus 1 (1 variants)
• Systemic lupus erythematosus (1 variants)
• TREX1-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TREX1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	113	7	121
missense	3	4	228	2		237
nonsense	7	4	2			13
start loss			6			6
frameshift	24	19	11			54
inframe indel	1	2	8			11
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding	1		27	10	3	41
Total	36	29	283	125	10

Highest pathogenic variant AF is 0.0000328

Variants in TREX1

This is a list of pathogenic ClinVar variants found in the TREX1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-48465821-T-C		Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Aicardi Goutieres syndrome	Likely benign (Jun 14, 2016)
3-48465824-TC-T		Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Aicardi Goutieres syndrome	Likely benign (Jun 14, 2016)
3-48466049-C-T		Aicardi Goutieres syndrome • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Uncertain significance (Jun 14, 2016)
3-48466130-G-T		Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Aicardi Goutieres syndrome	Uncertain significance (Jun 14, 2016)
3-48466137-A-G		Aicardi Goutieres syndrome • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Uncertain significance (Jun 14, 2016)
3-48466209-G-C		Aicardi Goutieres syndrome • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Uncertain significance (Jun 14, 2016)
3-48466219-C-T		Aicardi Goutieres syndrome • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Likely benign (Jun 14, 2016)
3-48466236-C-T		Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Aicardi-Goutieres syndrome 1	Uncertain significance (Jan 13, 2018)
3-48466268-T-C		Aicardi Goutieres syndrome • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Benign (Apr 24, 2018)
3-48466276-C-T		Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Aicardi-Goutieres syndrome 1	Likely benign (Apr 27, 2017)
3-48466285-ACTGC-A		Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Aicardi Goutieres syndrome	Uncertain significance (Jun 14, 2016)
3-48466520-G-A			Uncertain significance (Mar 16, 2018)
3-48466534-G-A		TREX1-related disorder	Uncertain significance (Nov 19, 2022)
3-48466535-G-T		TREX1-related disorder	Likely benign (Aug 27, 2024)
3-48466573-C-T		TREX1-related disorder	Uncertain significance (Oct 27, 2023)
3-48466578-C-T		Aicardi-Goutieres syndrome 1	Uncertain significance (Nov 07, 2019)
3-48466629-G-A		Aicardi-Goutieres syndrome 1 • TREX1-related disorder • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • not specified	Conflicting classifications of pathogenicity (Mar 19, 2024)
3-48466644-ACGTACCCAACCAT-A		Aicardi-Goutieres syndrome 1;Chilblain lupus 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Uncertain significance (Aug 12, 2022)
3-48466645-C-T		TREX1-related disorder	Uncertain significance (Sep 18, 2022)
3-48466656-A-G		Systemic lupus erythematosus • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Aicardi-Goutieres syndrome 1;Chilblain lupus 1	Conflicting classifications of pathogenicity (Sep 01, 2021)
3-48466657-T-C		Aicardi-Goutieres syndrome 1;Chilblain lupus 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	Uncertain significance (Mar 13, 2021)
3-48466657-TG-T		Aicardi-Goutieres syndrome 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Chilblain lupus 1	Pathogenic (Jan 18, 2024)
3-48466660-G-T		Aicardi-Goutieres syndrome 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Chilblain lupus 1	Uncertain significance (Nov 24, 2021)
3-48466661-C-T		Aicardi-Goutieres syndrome 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations;Chilblain lupus 1	Likely benign (Oct 08, 2023)
3-48466663-C-T		Aicardi-Goutieres syndrome 1;Chilblain lupus 1;Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations • Inborn genetic diseases	Uncertain significance (Jan 08, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TREX1	protein_coding	protein_coding	ENST00000422277	1	2600

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.575	0.415	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.821	240	207	1.16	0.0000118	2327
Missense in Polyphen		70	66.762	1.0485		803
Synonymous	-1.46	108	90.3	1.20	0.00000525	884
Loss of Function	2.07	1	6.84	0.146	3.85e-7	69

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini. Prevents cell-intrinsic initiation of autoimmunity. Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements. Unless degraded, these DNA fragments accumulate in the cytosol and activate the IFN-stimulatory DNA (ISD) response and innate immune signaling. Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates. Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light. During GZMA-mediated cell death, contributes to DNA damage in concert with NME1. NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair. {ECO:0000269|PubMed:10391904, ECO:0000269|PubMed:10393201, ECO:0000269|PubMed:16818237, ECO:0000269|PubMed:17293595, ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:23993650}.
• Disease: DISEASE: Aicardi-Goutieres syndrome 1 (AGS1) [MIM:225750]: A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. {ECO:0000269|PubMed:16845398, ECO:0000269|PubMed:17293595, ECO:0000269|PubMed:17357087, ECO:0000269|PubMed:17846997, ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:20799324, ECO:0000269|PubMed:23979357}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:17660818, ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:23979357}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV-light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto-immune reactivity and eventually skin lesions (PubMed:23993650). {ECO:0000269|PubMed:23993650}.; DISEASE: Chilblain lupus 1 (CHBL1) [MIM:610448]: A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade. {ECO:0000269|PubMed:17357087, ECO:0000269|PubMed:17440703}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vasculopathy, retinal, with cerebral leukodystrophy (RVCL) [MIM:192315]: A microvascular endotheliopathy resulting in central nervous system degeneration and retinopathy, with progressive loss of vision, stroke, motor impairment, and cognitive decline. The ocular manifestations are characterized by telangiectasias, microaneurysms and retinal capillary obliteration starting in the macula. Diseased cerebral white matter has prominent small infarcts that often coalesce to pseudotumors. {ECO:0000269|PubMed:17660820}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cytosolic DNA-sensing pathway - Homo sapiens (human);role of brca1 brca2 and atr in cancer susceptibility;regulation of cell cycle progression by plk3;STING mediated induction of host immune responses;Regulation by TREX1;Regulation of innate immune responses to cytosolic DNA;Innate Immune System;Immune System;IRF3-mediated induction of type I IFN;atm signaling pathway;Cytosolic sensors of pathogen-associated DNA (Consensus)

Recessive Scores

• pRec: 0.205

Intolerance Scores

• loftool: 0.174
• rvis_EVS: -0.67
• rvis_percentile_EVS: 15.76

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.146
• ghis: 0.456

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.908

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Trex1
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; respiratory system phenotype; liver/biliary system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: blood vessel development;kidney development;activation of immune response;macrophage activation involved in immune response;lymphoid progenitor cell differentiation;immunoglobulin biosynthetic process involved in immune response;immune response in brain or nervous system;inflammatory response to antigenic stimulus;T cell antigen processing and presentation;regulation of immunoglobulin production;heart morphogenesis;heart process;atrial cardiac muscle tissue development;generation of precursor metabolites and energy;regulation of glycolytic process;DNA metabolic process;DNA replication;DNA repair;mismatch repair;DNA modification;DNA catabolic process;DNA recombination;determination of adult lifespan;regulation of gene expression;regulation of fatty acid metabolic process;transposition, RNA-mediated;regulation of type I interferon production;DNA duplex unwinding;interferon-alpha production;regulation of tumor necrosis factor production;cellular response to reactive oxygen species;cellular response to interferon-beta;CD86 biosynthetic process;apoptotic cell clearance;regulation of cellular respiration;establishment of protein localization;regulation of lipid biosynthetic process;regulation of inflammatory response;regulation of catalytic activity;protein stabilization;regulation of T cell activation;defense response to virus;type I interferon signaling pathway;negative regulation of type I interferon-mediated signaling pathway;regulation of protein complex stability;cellular response to gamma radiation;detection of stimulus involved in cell cycle checkpoint;detection of DNA damage stimulus involved in DNA damage checkpoint;signal transduction involved in DNA damage checkpoint;cellular response to hydroxyurea;nucleic acid phosphodiester bond hydrolysis;immune complex formation;DNA synthesis involved in UV-damage excision repair;regulation of lysosome organization
• Cellular component: nuclear envelope;endoplasmic reticulum membrane;cytosol;oligosaccharyltransferase complex;protein-DNA complex;nuclear replication fork
• Molecular function: magnesium ion binding;double-stranded DNA binding;single-stranded DNA binding;3'-5'-exodeoxyribonuclease activity;DNA binding, bending;3'-5' exonuclease activity;exodeoxyribonuclease III activity;MutLalpha complex binding;MutSalpha complex binding;adenyl deoxyribonucleotide binding;protein homodimerization activity;metal ion binding;WW domain binding