IFIH1

interferon induced with helicase C domain 1, the group of Caspase recruitment domain containing|RNA helicases

Basic information

Region (hg38): 2:162267074-162318684

Links

ENSG00000115267 ∙ NCBI:64135 ∙ OMIM:606951 ∙ HGNC:18873 ∙ Uniprot:Q9BYX4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Aicardi-Goutieres syndrome 7 (Definitive), mode of inheritance: AD
• Singleton-Merten syndrome 1 (Strong), mode of inheritance: AD
• Aicardi-Goutieres syndrome 7 (Strong), mode of inheritance: AD
• Aicardi-Goutieres syndrome 7 (Definitive), mode of inheritance: AD
• Aicardi-Goutieres syndrome (Supportive), mode of inheritance: AD
• Singleton-Merten dysplasia (Supportive), mode of inheritance: AD
• Aicardi-Goutieres syndrome 7 (Strong), mode of inheritance: AD
• Singleton-Merten syndrome 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Aicardi-Goutieres syndrome 7; Singleton-Merten syndrome 1; Immunodeficiency 95	AD/AR	Allergy/Immunology/Infectious; Cardiovascular; Ophthalmologic; Pulmonary	Individuals with Aicardi-Goutieres syndrome may have pulmonary hypertension, and awareness may allow surveillance, prompt diagnosis of disease, and management of this sequelae; Among other manifestations, Singleton-Merton syndrome 1 can include cardiovascular calcifications, and awareness may allow early management (eg, surgical valvuloplasty has been described); Awareness of the risk of glaucoma in Singleton-Merton syndrome can allow surveillance, prompt awareness and treatment; Immunodeficiency 95 has been described as involving recurrent infection, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial	Allergy/Immunology/Infectious; Cardiovascular; Dental; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary	21070929; 23322711; 24686847; 24995871; 25243380; 25620204; 28716935; 30219631; 34185153

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IFIH1 gene.

• Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1 (2 variants)
• not provided (2 variants)
• Aicardi-Goutieres syndrome 7 (2 variants)
• Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7 (1 variants)
• Singleton-Merten syndrome 1 (1 variants)
• Neurodevelopmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IFIH1 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			5	209	10	224
missense	5	9	603	103	9	729
nonsense		3	26	8	1	38
start loss						0
frameshift		1	32	16		49
inframe indel			7			7
splice donor/acceptor (+/-2bp)		1	22	2		25
splice region			28	37	6	71
non coding			6	110	47	163
Total	5	14	701	448	67

Variants in IFIH1

This is a list of pathogenic ClinVar variants found in the IFIH1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-162267192-AT-A			Uncertain significance (Sep 01, 2022)
2-162267194-C-T			Benign (Apr 16, 2021)
2-162267209-A-G		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Likely benign (Mar 17, 2023)
2-162267210-T-G			Uncertain significance (Mar 27, 2023)
2-162267211-C-A		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Oct 13, 2023)
2-162267218-T-C		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Likely benign (Aug 18, 2022)
2-162267222-CA-C		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Uncertain significance (Mar 02, 2023)
2-162267228-T-C		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Uncertain significance (Apr 18, 2022)
2-162267234-T-C		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Aug 10, 2023)
2-162267236-G-A		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Likely benign (Apr 06, 2022)
2-162267236-G-C		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Uncertain significance (Oct 05, 2022)
2-162267242-A-T		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7 • Inborn genetic diseases	Likely benign (Jan 24, 2024)
2-162267243-T-C		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Sep 25, 2023)
2-162267252-G-C		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Aug 28, 2023)
2-162267253-T-C		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Dec 06, 2022)
2-162267258-G-T		not specified	Uncertain significance (May 03, 2020)
2-162267260-T-C		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Likely benign (Oct 06, 2023)
2-162267272-C-A		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Uncertain significance (Jun 20, 2022)
2-162267272-C-T		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Likely benign (Jul 07, 2023)
2-162267273-T-G		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Jan 19, 2024)
2-162267274-T-A			Uncertain significance (Jun 24, 2024)
2-162267275-T-G		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (May 23, 2023)
2-162267277-T-C		Aicardi-Goutieres syndrome 7;Singleton-Merten syndrome 1	Uncertain significance (Oct 20, 2023)
2-162267278-G-A		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Likely benign (Sep 15, 2022)
2-162267280-A-G		Singleton-Merten syndrome 1;Aicardi-Goutieres syndrome 7	Likely benign (Aug 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IFIH1	protein_coding	protein_coding	ENST00000263642	16	51625

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.98e-44	4.61e-9	120984	15	4749	125748	0.0191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.789	586	535	1.10	0.0000265	6804
Missense in Polyphen		195	181.68	1.0733		2333
Synonymous	-1.33	212	189	1.12	0.00000960	1852
Loss of Function	-1.57	59	47.3	1.25	0.00000242	624

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0326	0.0322
Ashkenazi Jewish	0.0191	0.0181
East Asian	0.00438	0.00425
Finnish	0.00405	0.00403
European (Non-Finnish)	0.0272	0.0267
Middle Eastern	0.00438	0.00425
South Asian	0.0153	0.0138
Other	0.0227	0.0221

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Its ligands include mRNA lacking 2'-O- methylation at their 5' cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines. {ECO:0000269|PubMed:14645903, ECO:0000269|PubMed:19211564, ECO:0000269|PubMed:19656871, ECO:0000269|PubMed:21217758, ECO:0000269|PubMed:21742966}.
• Disease: DISEASE: Diabetes mellitus, insulin-dependent, 19 (IDDM19) [MIM:610155]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16699517}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Note=IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD). {ECO:0000269|PubMed:19565506, ECO:0000269|PubMed:20015976}.; DISEASE: Aicardi-Goutieres syndrome 7 (AGS7) [MIM:615846]: 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:24686847, ECO:0000269|PubMed:24995871}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Singleton-Merten syndrome 1 (SGMRT1) [MIM:182250]: An autosomal dominant disorder with variable expression. Core features are marked aortic calcification, dental anomalies, osteopenia, acro-osteolysis, and to a lesser extent glaucoma, psoriasis, muscle weakness, and joint laxity. Dental anomalies include delayed eruption and immature root formation of anterior permanent teeth, early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss. Additional clinical manifestations include particular facial characteristics and abnormal joint and muscle ligaments. {ECO:0000269|PubMed:25620204}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Influenza A - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);RIG-I-like Receptor Signaling;NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10;Post-translational protein modification;TRAF6 mediated IRF7 activation;TRAF6 mediated NF-kB activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Metabolism of proteins;Innate Immune System;Immune System;TRAF3-dependent IRF activation pathway;Negative regulators of DDX58/IFIH1 signaling;Ub-specific processing proteases;Ovarian tumor domain proteases;Deubiquitination (Consensus)

Recessive Scores

• pRec: 0.252

Intolerance Scores

• loftool: 0.992
• rvis_EVS: 0.97
• rvis_percentile_EVS: 90.2

Haploinsufficiency Scores

• pHI: 0.576
• hipred: Y
• hipred_score: 0.675
• ghis: 0.552

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.649

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ifih1
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region 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); immune system phenotype; renal/urinary system phenotype; liver/biliary system phenotype; hematopoietic 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: detection of virus;response to virus;viral process;protein deubiquitination;protein sumoylation;negative regulation of type I interferon production;positive regulation of interferon-alpha production;positive regulation of interferon-beta production;regulation of type III interferon production;positive regulation of interferon-beta secretion;cytoplasmic pattern recognition receptor signaling pathway in response to virus;MDA-5 signaling pathway;innate immune response;defense response to virus;positive regulation of response to cytokine stimulus;cellular response to exogenous dsRNA;positive regulation of interferon-alpha secretion;positive regulation of tumor necrosis factor secretion;positive regulation of interleukin-6 secretion
• Cellular component: nucleus;cytosol
• Molecular function: DNA binding;double-stranded RNA binding;single-stranded RNA binding;helicase activity;protein binding;ATP binding;zinc ion binding;identical protein binding;ribonucleoprotein complex binding