IFIH1

protein-coding

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

Gene summary

IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome[provided by RefSeq, Jul 2020]

MANE transcript

NM_022168.4

Inheritance

AD, AR, SD

ClinVar variants

P:51U:951B:490

Top phenotype

Aicardi-Goutieres syndrome 7; Singleton-Merten syndrome 1; Immunodeficiency 95

gnomAD constraint

pLI —, LoF o/e 1.25

Max pathogenic AF

—

Genomic locus

chr2:162,267,074-162,318,684

External References & Databases

Ensembl (ENSG00000115267)

Transcript & Mutation Effects

hg38 • Region Span ~51.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

IFIH1-related type 1 interferonopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700262

Submitter: ClinGen

IFIH1 was first reported in relation to autosomal dominant type 1 interferonopathy in 2014 (Rice et al., PMID 24686847). Variants in IFIH1 have been reported with the following disease entities: Aicardi-Goutieres syndrome and Singleton-Merten syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability between the two disease entities. Therefore, Aicardi-Goutieres syndrome and Singleton-Merten syndrome have been lumped into one disease entity, “IFIH1-related type 1 interferonopathy” (MONDO:0700262). Type 1 interferonopathies are defined as conditions in which increased type 1 interferon signaling leads to autoimmune and neurological disorders. These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with variants in IFIH1 can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease. At least 44 pathogenic or likely pathogenic variants have been reported in humans. These variants have mostly been missense, although some nonsense and frameshift variants have also been reported. Evidence supporting this gene-disease relationship includes case level, segregation, and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 17 probands in 5 publications (PMIDs 24686847, 24995871, 25620204, 30219631, 31898846). Variants in this gene segregated with disease in 9 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is gain of function. This gene-disease relationship is supported by expression studies in vitro and in zebrafish (PMIDs 25620204, 38077314). In summary, there is definitive evidence to support the relationship between IFIH1 and autosomal dominant type 1 interferonopathy. 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 Leukodystrophy Gene Curation Expert Panel on the meeting date 07/22/2024 (SOP Version #10).

Singleton-Merten syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024535

Submitter: Labcorp Genetics (formerly Invitae)

Aicardi-Goutieres syndrome 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014367

Submitter: Labcorp Genetics (formerly Invitae)

Singleton-Merten dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008429

Submitter: Orphanet

Aicardi-Goutieres syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018866

Submitter: Orphanet

Singleton-Merten syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024535

Submitter: G2P

Aicardi-Goutieres syndrome 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014367

Submitter: Illumina

The IFIH1 gene is located on chromosome 2 at 2q24.2 and encodes the interferon induced with helicase C domain 1 protein which is associated with innate immunity. This protein identifies and attaches to double stranded RNA from certain viruses, forming a filament which stimulates the induction of interferon and proinflammatory cytokines. The IFIH1 gene was first reported in relation to autosomal dominant Aicardi-Goutieres syndrome in 2014 (24686847: Rice et al. 2014). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least five unique missense variants in this gene have been reported in at least three publications (24686847: Rice et al. 2014; 24995871: Oda et al. 2014; 30219631: Adang et al. 2018). Most variants were confirmed to be de novo; however, in one case the variant was inherited from a clinically asymptomatic father (24686847: Rice et al. 2014). The maximum score for genetic evidence has been reached. This gene-disease relationship is supported by functional alteration in non-patient and patient cells demonstrating disease-associated IFIH1 variants result in excessive interferon signalling, suggesting gain-of-function as the disease mechanism (24686847: Rice et al. 2014). Homozygous knockout mice show impaired interferon signalling in response to picornavirus infection (16625202: Kato et al. 2006). In summary, IFIH1 is definitively associated with Aicardi-Goutieres syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Aicardi-Goutieres syndrome 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014367

Submitter: G2P

immunodeficiency 95LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030692

Submitter: Ambry Genetics

Aicardi-Goutieres syndrome 7STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0014367

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Aicardi-Goutieres syndrome 7; Singleton-Merten syndrome 1; Immunodeficiency 95AD/AR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dental; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Ophthalmologic; Pulmonary

Rationale: 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

Refs: 21070929; 23322711; 24686847; 24995871; 25243380; 25620204; 28716935; 30219631; 34185153

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IFIH1 variants in ClinVar

32 Conditions Cataloged

Aicardi-Goutieres syndrome 7Total: 1547

Singleton-Merten syndrome 1Total: 1513

not providedTotal: 385

not specifiedTotal: 158

Inborn genetic diseasesTotal: 138

IFIH1-related disorderTotal: 85

Immunodeficiency 95Total: 60

See casesTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022168.4. 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	284 clinvar	2 clinvar	293
missense	24 clinvar	15 clinvar	827 clinvar	149 clinvar	1 clinvar	1016
nonsense		4 clinvar	36 clinvar	19 clinvar		59
start loss			2 clinvar			2
frameshift		5 clinvar	45 clinvar	31 clinvar		81
splice donor/acceptor (+/-2bp)		3 clinvar	34 clinvar	3 clinvar	1 clinvar	41
Total	24	27	951	486	4	1492

Highest pathogenic variant AF is 0.000017504879

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022168.4	RefSeq	NP_071451.2	16	MANE Select
ENST00000649979.2	Ensembl	ENSP00000497271.1	16	MANE Select
ENST00000421365.2	Ensembl	ENSP00000408450.2	2	Standard
ENST00000648433.1	Ensembl	ENSP00000496816.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

detection of virus
response to virus
viral process
protein deubiquitination
protein sumoylation

Molecular Function

DNA binding
double-stranded RNA binding
single-stranded RNA binding
helicase activity
protein binding

Cellular Component

nucleus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263642
Coding exons: 16
Length: 51625
Individuals with no LoFs: 120984
Homozygous LoFs: 15
Heterozygous LoFs: 4749
Defined: 125748
p: 0.0191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.789	586	535	1.10	0.0000265	6804
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.012	0.012	notable
Latino/Admixed American	0.021	0.020	notable
Ashkenazi Jewish	0.019	0.018	notable
East Asian	0.0044	0.0042	notable
Finnish	0.0041	0.0040	notable
European (Non-Finnish)	0.027	0.027	notable
South Asian	0.015	0.014	notable
Other	0.023	0.022	notable

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.252

Intolerance Scores

LoFtool: 0.992
RVIS EVS: 0.97
RVIS percentile EVS: 90.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.649

Gene Damage Prediction

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