2-162281473-T-C

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.1379A>G(p.His460Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0475 in 1,611,932 control chromosomes in the GnomAD database, including 10,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H460Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 4261 hom., cov: 32)

Exomes 𝑓: 0.037 ( 6458 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.05

Publications

51 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=0.0037111044).

BP6

Variant 2-162281473-T-C is Benign according to our data. Variant chr2-162281473-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.1379A>G	p.His460Arg	missense_variant	Exon 7 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1 link	c.662A>G	p.His221Arg	missense_variant	Exon 6 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.1379A>G	p.His460Arg	missense_variant	Exon 7 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23046

AN:

151878

Hom.:

4215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.0248

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.0967

AC:

24216

AN:

250532

AF XY:

0.0762

show subpopulations

Gnomad AFR exome

AF:

0.427

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0619

GnomAD4 exome

AF:

0.0366

AC:

53415

AN:

1459936

Hom.:

6458

Cov.:

AF XY:

0.0334

AC XY:

24280

AN XY:

726314

show subpopulations

African (AFR)

AF:

0.424

AC:

14133

AN:

33342

American (AMR)

AF:

0.332

AC:

14788

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00783

AC:

204

AN:

26068

East Asian (EAS)

AF:

0.139

AC:

5529

AN:

39652

South Asian (SAS)

AF:

0.0221

AC:

1908

AN:

86218

European-Finnish (FIN)

AF:

0.0154

AC:

824

AN:

53346

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0114

AC:

12660

AN:

1110776

Other (OTH)

AF:

0.0546

AC:

3288

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1990

3979

5969

7958

9948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

880

1760

2640

3520

4400

<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:

0.152

AC:

23167

AN:

151996

Hom.:

4261

Cov.:

AF XY:

0.152

AC XY:

11293

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.416

AC:

17245

AN:

41438

American (AMR)

AF:

0.251

AC:

3827

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3468

East Asian (EAS)

AF:

0.124

AC:

638

AN:

5160

South Asian (SAS)

AF:

0.0247

AC:

119

AN:

4826

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

888

AN:

67940

Other (OTH)

AF:

0.136

AC:

287

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

753

1505

2258

3010

3763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.0575

Hom.:

5143

Bravo

AF:

0.188

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.415

AC:

1828

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.0927

AC:

11244

Asia WGS

AF:

0.128

AC:

445

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 03, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23441136) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

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 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.057

T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.035

.;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.4

N;N;.

PhyloP100

5.1

PrimateAI

Benign

0.48

PROVEAN

Benign

2.5

.;N;.

REVEL

Benign

0.11

Sift

Benign

1.0

.;T;.

Sift4G

Benign

1.0

.;T;.

Polyphen

0.0

B;B;.

Vest4

0.051

MPC

0.027

ClinPred

0.0054

GERP RS

5.9

Varity_R

0.18

gMVP

0.59

Mutation Taster

=84/16

polymorphism (auto)

(source)

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

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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