NM_022168.4:c.2785G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_022168.4(IFIH1):c.2785G>A(p.Val929Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000652 in 1,606,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.59

Publications

5 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010380626).

BP6

Variant 2-162268109-C-T is Benign according to our data. Variant chr2-162268109-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00192 (292/152278) while in subpopulation AFR AF = 0.00597 (248/41562). AF 95% confidence interval is 0.00536. There are 1 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2785G>A	p.Val929Ile	missense	Exon 14 of 16	NP_071451.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFIH1	ENST00000649979.2	MANE Select	c.2785G>A	p.Val929Ile	missense	Exon 14 of 16	ENSP00000497271.1
IFIH1	ENST00000648433.1		c.2668G>A	p.Val890Ile	missense	Exon 13 of 15	ENSP00000496816.1
IFIH1	ENST00000679938.1		c.2473G>A	p.Val825Ile	missense	Exon 13 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

291

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00596

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000556

AC:

136

AN:

244692

AF XY:

0.000431

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.000358

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

AF:

0.000520

AC:

756

AN:

1453886

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

370

AN XY:

722948

show subpopulations

African (AFR)

AF:

0.00523

AC:

173

AN:

33050

American (AMR)

AF:

0.000393

AC:

AN:

43280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25812

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000475

AC:

AN:

84134

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.000874

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000433

AC:

480

AN:

1109006

Other (OTH)

AF:

0.00120

AC:

AN:

60112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.00192

AC:

292

AN:

152278

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00597

AC:

248

AN:

41562

American (AMR)

AF:

0.00111

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000926

Hom.:

Bravo

AF:

0.00237

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.046

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

3.0

PhyloP100

5.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.89

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.32

MVP

0.65

MPC

0.10

ClinPred

0.076

GERP RS

4.7

Varity_R

0.70

gMVP

0.51

Mutation Taster

=57/43

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over