2-162267273-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022168.4(IFIH1):c.3005A>C(p.Lys1002Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. K1002N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.3005A>C	p.Lys1002Thr	missense_variant	16/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.2288A>C	p.Lys763Thr	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.3005A>C	p.Lys1002Thr	missense_variant	16/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1002 of the IFIH1 protein (p.Lys1002Thr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IFIH1 protein function. 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
Polyphen		0.86	P;P;.
Vest4		0.48
MutPred		0.47		Loss of methylation at K1002 (P = 0.0028);Loss of methylation at K1002 (P = 0.0028);.;
MVP		0.78
MPC		0.19
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.82
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-163123783;