2-162267258-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022168.4(IFIH1):c.3020C>A(p.Pro1007His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.3020C>A	p.Pro1007His	missense_variant	16/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.2303C>A	p.Pro768His	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.3020C>A	p.Pro1007His	missense_variant	16/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.0037	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.57	T
Polyphen		1.0	D;D;.
Vest4		0.27
MutPred		0.71		Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);.;
MVP		0.77
MPC		0.044
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.49

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: rs1690942194; hg19: chr2-163123768;