2-162282558-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

IFIH1
NM_022168.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.34
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3870566).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IFIH1NM_022168.4 linkc.1114C>G p.Leu372Val missense_variant Exon 6 of 16 ENST00000649979.2 NP_071451.2 Q9BYX4-1
IFIH1XM_047445407.1 linkc.397C>G p.Leu133Val missense_variant Exon 5 of 15 XP_047301363.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IFIH1ENST00000649979.2 linkc.1114C>G p.Leu372Val missense_variant Exon 6 of 16 NM_022168.4 ENSP00000497271.1 Q9BYX4-1

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
LINK: link

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 v4.3

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;T;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.39
T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.33
N;N;.
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;P;.
Vest4
0.51
MutPred
0.58
Gain of MoRF binding (P = 0.1133);Gain of MoRF binding (P = 0.1133);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-163139068; API