rs1553696482

Positions:

• chr2-162267342-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_022168.4(IFIH1):​c.2936T>G​(p.Leu979Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L979L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-162267342-A-C is Pathogenic according to our data. Variant chr2-162267342-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 541770.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.2936T>G	p.Leu979Trp	missense_variant	16/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.2219T>G	p.Leu740Trp	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.2936T>G	p.Leu979Trp	missense_variant	16/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects IFIH1 protein function (PMID: 31898846). This variant has been observed in individual(s) with clinical features of Aicardi Goutieres syndrome (PMID: 31898846, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 541770). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with tryptophan at codon 979 of the IFIH1 protein (p.Leu979Trp). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	D;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.45	T
Polyphen		1.0	D;D;.
Vest4		0.65
MutPred		0.56		Gain of MoRF binding (P = 0.0512);Gain of MoRF binding (P = 0.0512);.;
MVP		0.76
MPC		0.24
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.54
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553696482; hg19: chr2-163123852;