2-162282494-T-C

Variant summary

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

The NM_022168.4(IFIH1):ā€‹c.1178A>Gā€‹(p.Asp393Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,778 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

1
10
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.60
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IFIH1NM_022168.4 linkuse as main transcriptc.1178A>G p.Asp393Gly missense_variant 6/16 ENST00000649979.2 NP_071451.2
IFIH1XM_047445407.1 linkuse as main transcriptc.461A>G p.Asp154Gly missense_variant 5/15 XP_047301363.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IFIH1ENST00000649979.2 linkuse as main transcriptc.1178A>G p.Asp393Gly missense_variant 6/16 NM_022168.4 ENSP00000497271 P1Q9BYX4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249814
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135064
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459778
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000111
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.086
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
.;D;D
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.58
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;L;.
MutationTaster
Benign
0.88
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-5.1
.;D;.
REVEL
Benign
0.25
Sift
Uncertain
0.0040
.;D;.
Sift4G
Uncertain
0.0080
.;D;.
Polyphen
1.0
D;D;.
Vest4
0.66
MutPred
0.57
Gain of MoRF binding (P = 0.0724);Gain of MoRF binding (P = 0.0724);Gain of MoRF binding (P = 0.0724);
MVP
0.71
MPC
0.21
ClinPred
0.98
D
GERP RS
5.8
Varity_R
0.84
gMVP
0.67

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777449; hg19: chr2-163139004; API