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GeneBe

rs1990760

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022168.4(IFIH1):c.2836G>A(p.Ala946Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,609,886 control chromosomes in the GnomAD database, including 262,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 18236 hom., cov: 33)
Exomes 𝑓: 0.57 ( 244347 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.750
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=2.7895177E-5).
BP6
Variant 2-162267541-C-T is Benign according to our data. Variant chr2-162267541-C-T is described in ClinVar as [Benign]. Clinvar id is 261566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IFIH1NM_022168.4 linkuse as main transcriptc.2836G>A p.Ala946Thr missense_variant 15/16 ENST00000649979.2
IFIH1XM_047445407.1 linkuse as main transcriptc.2119G>A p.Ala707Thr missense_variant 14/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IFIH1ENST00000649979.2 linkuse as main transcriptc.2836G>A p.Ala946Thr missense_variant 15/16 NM_022168.4 P1Q9BYX4-1

Frequencies

GnomAD3 genomes
AF:
0.452
AC:
68651
AN:
151970
Hom.:
18242
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.186
Gnomad AMI
AF:
0.574
Gnomad AMR
AF:
0.443
Gnomad ASJ
AF:
0.462
Gnomad EAS
AF:
0.195
Gnomad SAS
AF:
0.514
Gnomad FIN
AF:
0.568
Gnomad MID
AF:
0.491
Gnomad NFE
AF:
0.610
Gnomad OTH
AF:
0.471
GnomAD3 exomes
AF:
0.502
AC:
125999
AN:
251196
Hom.:
34569
AF XY:
0.515
AC XY:
69974
AN XY:
135774
show subpopulations
Gnomad AFR exome
AF:
0.175
Gnomad AMR exome
AF:
0.424
Gnomad ASJ exome
AF:
0.454
Gnomad EAS exome
AF:
0.174
Gnomad SAS exome
AF:
0.533
Gnomad FIN exome
AF:
0.572
Gnomad NFE exome
AF:
0.606
Gnomad OTH exome
AF:
0.529
GnomAD4 exome
AF:
0.569
AC:
830046
AN:
1457798
Hom.:
244347
Cov.:
34
AF XY:
0.570
AC XY:
413369
AN XY:
725498
show subpopulations
Gnomad4 AFR exome
AF:
0.166
Gnomad4 AMR exome
AF:
0.426
Gnomad4 ASJ exome
AF:
0.452
Gnomad4 EAS exome
AF:
0.202
Gnomad4 SAS exome
AF:
0.529
Gnomad4 FIN exome
AF:
0.575
Gnomad4 NFE exome
AF:
0.609
Gnomad4 OTH exome
AF:
0.529
GnomAD4 genome
AF:
0.451
AC:
68647
AN:
152088
Hom.:
18236
Cov.:
33
AF XY:
0.448
AC XY:
33329
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.185
Gnomad4 AMR
AF:
0.442
Gnomad4 ASJ
AF:
0.462
Gnomad4 EAS
AF:
0.195
Gnomad4 SAS
AF:
0.515
Gnomad4 FIN
AF:
0.568
Gnomad4 NFE
AF:
0.610
Gnomad4 OTH
AF:
0.468
Alfa
AF:
0.563
Hom.:
62070
Bravo
AF:
0.424
TwinsUK
AF:
0.598
AC:
2217
ALSPAC
AF:
0.605
AC:
2330
ESP6500AA
AF:
0.185
AC:
816
ESP6500EA
AF:
0.603
AC:
5185
ExAC
AF:
0.505
AC:
61267
Asia WGS
AF:
0.326
AC:
1136
AN:
3478
EpiCase
AF:
0.596
EpiControl
AF:
0.586

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanNov 12, 2023This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Aicardi-Goutieres syndrome 7 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2018This variant is associated with the following publications: (PMID: 31866997, 22561518, 28553952, 28973304, 23441136, 27720759, 28000722, 23734776, 16699517, 24386202, 20644636, 20694011, 20467774, 17535987, 19324880, 21705624, 19539001, 18927125, 19841890, 24117221, 24995871) -
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Singleton-Merten syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.71
T
BayesDel_noAF
Benign
-0.65
Cadd
Benign
11
Dann
Benign
0.76
DEOGEN2
Benign
0.028
T;T;.
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.64
D
MetaRNN
Benign
0.000028
T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.6
L;L;.
MutationTaster
Benign
0.21
P;P
PrimateAI
Benign
0.29
T
Polyphen
0.10
B;B;.
Vest4
0.017
MPC
0.024
ClinPred
0.0023
T
GERP RS
3.9
Varity_R
0.075
gMVP
0.23

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: rs1990760; hg19: chr2-163124051; COSMIC: COSV55125663; API