2-162288167-C-T

Variant names:

• chr2-162288167-C-T
• rs887114201
• NM_022168.4:c.1063G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022168.4(IFIH1):​c.1063G>A​(p.Glu355Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E355E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.963
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057969242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.1063G>A	p.Glu355Lys	missense_variant	Exon 5 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.346G>A	p.Glu116Lys	missense_variant	Exon 4 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.1063G>A	p.Glu355Lys	missense_variant	Exon 5 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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

Mar 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 576956). 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. This variant has not been reported in the literature in individuals affected with IFIH1-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 355 of the IFIH1 protein (p.Glu355Lys). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	.;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.075	N;N;.
PhyloP100		0.96
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.38	.;N;.
REVEL	Benign	0.094
Sift	Benign	0.15	.;T;.
Sift4G	Benign	0.29	.;T;.
Polyphen		0.061	B;B;.
Vest4		0.20
MutPred		0.43		Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);
MVP		0.58
MPC		0.027
ClinPred		0.24	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.41
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs887114201; hg19: chr2-163144677;