2-162282558-G-C

Variant names:

• chr2-162282558-G-C
• rs587777576
• NM_022168.4:c.1114C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_022168.4(IFIH1):​c.1114C>G​(p.Leu372Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L372F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-162282558-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 140751.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3870566).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.1114C>G	p.Leu372Val	missense	Exon 6 of 16	NP_071451.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.1114C>G	p.Leu372Val	missense	Exon 6 of 16	ENSP00000497271.1
	IFIH1	ENST00000648433.1		c.1114C>G	p.Leu372Val	missense	Exon 6 of 15	ENSP00000496816.1
	IFIH1	ENST00000679938.1		c.802C>G	p.Leu268Val	missense	Exon 5 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 372 of the IFIH1 protein (p.Leu372Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IFIH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1484381). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt IFIH1 function with a negative predictive value of 95%. This variant disrupts the p.Leu372 amino acid residue in IFIH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24995871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.33	N
PhyloP100		9.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.20
Sift	Benign	0.20	T
Sift4G	Benign	0.16	T
Polyphen		0.81	P
Vest4		0.51
MutPred		0.58		Gain of MoRF binding (P = 0.1133)
MVP		0.48
MPC		0.057
ClinPred		0.67	D
GERP RS		5.8
Varity_R		0.45
gMVP		0.52
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777576; hg19: chr2-163139068;