2-162277435-AATCT-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 8P and 12B. PVS1BP6_Very_StrongBS1

The NM_022168.4(IFIH1):c.2020_2023delAGAT(p.Arg674PhefsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000147 in 1,608,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 frameshift

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 2-162277435-AATCT-A is Benign according to our data. Variant chr2-162277435-AATCT-A is described in ClinVar as [Likely_benign]. Clinvar id is 377097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000131 (20/152272) while in subpopulation AMR AF= 0.00118 (18/15290). AF 95% confidence interval is 0.000761. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.2020_2023delAGAT	p.Arg674PhefsTer3	frameshift_variant	Exon 10 of 16	ENST00000649979.2	NP_071451.2	Q9BYX4-1
IFIH1	XM_047445407.1 link	c.1303_1306delAGAT	p.Arg435PhefsTer3	frameshift_variant	Exon 9 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.2020_2023delAGAT	p.Arg674PhefsTer3	frameshift_variant	Exon 10 of 16		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000726

AC:

179

AN:

246470

Hom.:

AF XY:

0.000593

AC XY:

AN XY:

133160

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000148

AC:

216

AN:

1456666

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

724652

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.00417

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000583

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000992

Gnomad4 OTH exome

AF:

0.000183

GnomAD4 genome

AF:

0.000131

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000113

Hom.:

Bravo

AF:

0.000272

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95

Benign:1

Nov 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jul 07, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IFIH1-related disorder

Benign:1

Mar 03, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over