rs765985079

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_022168.4(IFIH1):​c.1166G>A​(p.Gly389Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,459,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.71
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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21186876).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IFIH1NM_022168.4 linkuse as main transcriptc.1166G>A p.Gly389Glu missense_variant 6/16 ENST00000649979.2 NP_071451.2
IFIH1XM_047445407.1 linkuse as main transcriptc.449G>A p.Gly150Glu 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.1166G>A p.Gly389Glu missense_variant 6/16 NM_022168.4 ENSP00000497271 P1Q9BYX4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249636
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134988
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:
0.00000888
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1459734
Hom.:
0
Cov.:
30
AF XY:
0.0000234
AC XY:
17
AN XY:
726248
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:
0.0000288
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000586
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 05, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 15, 2021Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 25, 2023This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 389 of the IFIH1 protein (p.Gly389Glu). This variant is present in population databases (rs765985079, gnomAD 0.002%). 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: 291088). 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 80%. 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. -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
IFIH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 30, 2022The IFIH1 c.1166G>A variant is predicted to result in the amino acid substitution p.Gly389Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-163139016-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.84
.;T;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.82
L;L;.
MutationTaster
Benign
0.66
D;D
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.6
.;N;.
REVEL
Benign
0.17
Sift
Benign
0.15
.;T;.
Sift4G
Benign
0.65
.;T;.
Polyphen
0.98
D;D;.
Vest4
0.78
MVP
0.65
MPC
0.17
ClinPred
0.68
D
GERP RS
4.0
Varity_R
0.41
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs765985079; hg19: chr2-163139016; API