rs35667974

Positions:

Variant summary

Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar 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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 474954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162268127-T-C is described in Lovd as [Likely_benign]. Variant chr2-162268127-T-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.2767A>G	p.Ile923Val	missense_variant	14/16	ENST00000649979.2	NP_071451.2	Q9BYX4-1
IFIH1	XM_047445407.1 link	c.2050A>G	p.Ile684Val	missense_variant	13/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.2767A>G	p.Ile923Val	missense_variant	14/16		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

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

GnomAD3 exomes

AF:

0.0113

AC:

2789

AN:

247356

Hom.:

AF XY:

0.0109

AC XY:

1450

AN XY:

133634

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 SAS exome

AF:

0.000170

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

Gnomad4 AFR exome

AF:

0.00250

Gnomad4 AMR exome

AF:

0.00226

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000200

Gnomad4 FIN exome

AF:

0.0200

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.0114

AC:

1739

AN:

152342

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

801

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00349

Gnomad4 AMR

AF:

0.00300

Gnomad4 ASJ

AF:

0.0109

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.0161

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	This variant is associated with the following publications: (PMID: 20736039, 20668468, 19264985, 19324880, 27720759, 28501801, 28973304, 28658209) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 20, 2017

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

IFIH1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2022

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

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;.

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

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

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