rs376048533

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-162272377-C-G
• chr2-162272377-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_022168.4(IFIH1):​c.2465G>C​(p.Arg822Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 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. R822Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.60
• Publications: 0 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 12 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 2-162272377-C-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.2465G>C	p.Arg822Pro	missense_variant	Exon 13 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1748G>C	p.Arg583Pro	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>C	p.Arg822Pro	missense_variant	Exon 13 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459800 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726194

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

American (AMR) AF: 0.00 AC: 0 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: 9.00e-7 AC: 1 AN: 1111052

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2023

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The maternally inherited heterozygous c.2465G>C p.(Arg822Pro) variant in the IFIH1 gene has not previously been reported in the literature or public variant repositories (ClinVar and LOVD) and is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.2465G>C variant in IFIH1 is located in exon 13 of this 16-exon gene, and predicted to replace an evolutionarily conserved arginine amino acid with proline at position 822 in the Helicase C-terminal domain of the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg822Pro) [REVEL = 0.986]. A different amino acid change at the same position (c.2465G>A p.(Arg822Gln)) has been deposited in ClinVar as Pathogenic [ClinVarID:189338, multiple submissions] and it has been reported in families with Singleton-Merten syndrome (de novo or inherited with variable interfamilial and intrafamilial phenotypes) [PMID: 25620204, 35410415, 28319323, 35754802, 27943079]; de novo in a patient with Aicardi-Goutières syndrome [PMID: 28475458]; and de novo in a patient with developmental delay, spastic dystonia and intracranial calcifications [PMID: 31898846]. While the variant identified in this fetus is inherited from the unaffected mother, both reduced penetrance and variable expressivity have been reported in families with pathogenic IFIH1 variants [PMID: 31898846, 24686847]. Interferon activity is often abnormal in individuals with pathogenic IFIH1 variants, and assessment of these laboratory parameters may be useful in further delineating the pathogenicity of this variant. Based on available evidence, this maternally inherited c.2465G>C p.(Arg822Pro) variant identified in IFIH1 is classified here as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	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	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;.
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.6	.;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.0020	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.87		Loss of methylation at R822 (P = 0.0112);Loss of methylation at R822 (P = 0.0112);.;
MVP		0.97
MPC		0.23
ClinPred		1.0	D
GERP RS		5.9
Varity_R		1.0
gMVP		0.96
Mutation Taster		=23/77	disease causing

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;