2-162272377-C-T

Variant names:

• chr2-162272377-C-T
• rs376048533
• NM_022168.4:c.2465G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_022168.4(IFIH1):​c.2465G>A​(p.Arg822Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,459,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R822P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.60
• Publications: 30 publications found

Genes affected

IFIH1 (HGNC:18873): (interferon induced with helicase C domain 1) 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]

IFIH1 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), G2P
• Singleton-Merten syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Singleton-Merten dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 95

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_022168.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-162272377-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3235948.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 2-162272377-C-T is Pathogenic according to our data. Variant chr2-162272377-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.2465G>A	p.Arg822Gln	missense_variant	Exon 13 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1748G>A	p.Arg583Gln	missense_variant	Exon 12 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.2465G>A	p.Arg822Gln	missense_variant	Exon 13 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 249178 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459800 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726194

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.0000227 AC: 1 AN: 44078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111052

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000215 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Sep 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the R822Q variant is gain-of-function with increased interferon beta expression (Rutsch et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25620204, 26284909, 28475458, 28319323, 31898846, 34426522, 31589614) -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IFIH1: PP1:Strong, PS2, PS4:Moderate, PS3:Supporting -

Nov 04, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP2, PM2_SUP, PS3 -

Singleton-Merten syndrome 1 Pathogenic:3

Jul 28, 2023

Molecular Medicine, University of Pavia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25620204). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189338 / PMID: 25620204). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25620204). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25620204). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aicardi-Goutieres syndrome 7 Pathogenic:2

Oct 02, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PS3, PP1, PP3, PP5 -

Feb 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Pathogenic:2

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 822 of the IFIH1 protein (p.Arg822Gln). This variant is present in population databases (rs376048533, gnomAD 0.005%). This missense change has been observed in individuals with Singleton–Merten syndrome (PMID: 25620204, 28319323). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189338). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt IFIH1 function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects IFIH1 function (PMID: 25620204). For these reasons, this variant has been classified as Pathogenic. -

Feb 28, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Incidental Discovery Pathogenic:1

Apr 24, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Feb 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2465G>A (p.R822Q) alteration is located in exon 13 (coding exon 13) of the IFIH1 gene. This alteration results from a G to A substitution at nucleotide position 2465, causing the arginine (R) at amino acid position 822 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/249178) total alleles studied. The highest observed frequency was 0.017% (1/6050) of Other alleles. This variant was identified in one or more individuals with features consistent with IFIH1-related interferonopathy (Rutsch, 2015; Pettersson, 2017) and segregated with disease in at least one family. This variant was also determined to be de novo in at least one individual with features consistent with IFIH1-related interferonopathy (Rutsch, 2015; Buers, 2017; Riou, 2022; Broser, 2022). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing IFIH1 function, this variant showed functionally abnormal results (Rutsch, 2015; Emralino, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

IFIH1-related disorder Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IFIH1 c.2465G>A variant is predicted to result in the amino acid substitution p.Arg822Gln. This variant has been reported as segregating with disease in kindreds with Singleton-Merten syndrome (Rutsch et al. 2015. PubMed ID: 25620204; Pettersson et al. 2017. PubMed ID: 28319323). This variant has also been reported as de novo in an individual with Singleton-Merten syndrome (Broser et al. 2022. PubMed ID: 35410415). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;.
PhyloP100		7.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.020	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.99
MVP		0.96
MPC		0.21
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.90
Mutation Taster		=47/53	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs376048533; hg19: chr2-163128887;