NM_022168.4:c.2836G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.750

Publications

391 publications found

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]

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

IFIH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.2836G>A	p.Ala946Thr	missense_variant	Exon 15 of 16	ENST00000649979.2	NP_071451.2	Q9BYX4-1
IFIH1	XM_047445407.1 link	c.2119G>A	p.Ala707Thr	missense_variant	Exon 14 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.2836G>A	p.Ala946Thr	missense_variant	Exon 15 of 16		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.452

AC:

68651

AN:

151970

Hom.:

18242

Cov.:

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

GnomAD2 exomes

AF:

0.502

AC:

125999

AN:

251196

AF XY:

0.515

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 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.:

AF XY:

0.570

AC XY:

413369

AN XY:

725498

show subpopulations

African (AFR)

AF:

0.166

AC:

5550

AN:

33452

American (AMR)

AF:

0.426

AC:

19016

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

11797

AN:

26114

East Asian (EAS)

AF:

0.202

AC:

8006

AN:

39684

South Asian (SAS)

AF:

0.529

AC:

45573

AN:

86166

European-Finnish (FIN)

AF:

0.575

AC:

30693

AN:

53388

Middle Eastern (MID)

AF:

0.502

AC:

2890

AN:

5762

European-Non Finnish (NFE)

AF:

0.609

AC:

674622

AN:

1108294

Other (OTH)

AF:

0.529

AC:

31899

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

16355

32709

49064

65418

81773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17828

35656

53484

71312

89140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.451

AC:

68647

AN:

152088

Hom.:

18236

Cov.:

AF XY:

0.448

AC XY:

33329

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.185

AC:

7689

AN:

41472

American (AMR)

AF:

0.442

AC:

6761

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

1602

AN:

3468

East Asian (EAS)

AF:

0.195

AC:

1010

AN:

5170

South Asian (SAS)

AF:

0.515

AC:

2489

AN:

4830

European-Finnish (FIN)

AF:

0.568

AC:

6006

AN:

10574

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.610

AC:

41433

AN:

67976

Other (OTH)

AF:

0.468

AC:

990

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1693

3386

5078

6771

8464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

620

1240

1860

2480

3100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.548

Hom.:

112098

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aicardi-Goutieres syndrome 7

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Singleton-Merten syndrome 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.028

T;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.69

.;T;T

MetaRNN

Benign

0.000028

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

0.75

PrimateAI

Benign

0.29

PROVEAN

Benign

0.19

.;N;.

REVEL

Benign

0.036

Sift

Benign

0.51

.;T;.

Sift4G

Benign

0.62

.;T;.

Polyphen

0.10

B;B;.

Vest4

0.017

MPC

0.024

ClinPred

0.0023

GERP RS

3.9

Varity_R

0.075

gMVP

0.23

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over