2-162268127-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022168.4(IFIH1):c.2767A>G(p.Ile923Val) variant causes a missense change. The variant allele was found at a frequency of 0.0164 in 1,609,266 control chromosomes in the GnomAD database, including 279 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I923T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 263 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.71

Publications

106 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=0.007831156).

BP6

Variant 2-162268127-T-C is Benign according to our data. Variant chr2-162268127-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1739/152342) while in subpopulation NFE AF = 0.0188 (1281/68034). AF 95% confidence interval is 0.018. There are 16 homozygotes in GnomAd4. There are 801 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.2767A>G	p.Ile923Val	missense_variant	Exon 14 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1 link	c.2050A>G	p.Ile684Val	missense_variant	Exon 13 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.2767A>G	p.Ile923Val	missense_variant	Exon 14 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1738

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00350

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.0113

AC:

2789

AN:

247356

AF XY:

0.0109

show subpopulations

Gnomad AFR exome

AF:

0.00248

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00986

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0205

Gnomad NFE exome

AF:

0.0183

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0169

AC:

24651

AN:

1456924

Hom.:

263

Cov.:

AF XY:

0.0163

AC XY:

11801

AN XY:

724584

show subpopulations

African (AFR)

AF:

0.00250

AC:

AN:

33208

American (AMR)

AF:

0.00226

AC:

AN:

43798

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

285

AN:

25964

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39554

South Asian (SAS)

AF:

0.000200

AC:

AN:

84940

European-Finnish (FIN)

AF:

0.0200

AC:

1064

AN:

53328

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0201

AC:

22362

AN:

1110168

Other (OTH)

AF:

0.0123

AC:

738

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1060

2120

3181

4241

5301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.0114

AC:

1739

AN:

152342

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

801

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00349

AC:

145

AN:

41572

American (AMR)

AF:

0.00300

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0208

AC:

221

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0188

AC:

1281

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0160

Hom.:

Bravo

AF:

0.0100

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0163

AC:

140

ExAC

AF:

0.0115

AC:

1399

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 15, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20736039, 20668468, 19264985, 19324880, 27720759, 28501801, 28973304, 28658209) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 20, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

IFIH1-related disorder

Benign:1

Aug 18, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

T;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

5.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.40

.;N;.

REVEL

Benign

0.12

Sift

Benign

0.20

.;T;.

Sift4G

Benign

0.28

.;T;.

Polyphen

0.96

D;D;.

Vest4

0.29

MPC

0.18

ClinPred

0.027

GERP RS

5.1

Varity_R

0.30

gMVP

0.47

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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