2-162288184-T-C

Position:

chr2-162288184-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022168.4(IFIH1):c.1046A>G(p.Lys349Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,674 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 36 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.33

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:

IFIH1 (HGNC:):

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=0.0059061646).

BP6

Variant 2-162288184-T-C is Benign according to our data. Variant chr2-162288184-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 541789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162288184-T-C is described in Lovd as [Benign]. Variant chr2-162288184-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00176 (267/152054) while in subpopulation SAS AF= 0.0213 (103/4832). AF 95% confidence interval is 0.018. There are 3 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4 linkuse as main transcript	c.1046A>G	p.Lys349Arg	missense_variant	5/16	ENST00000649979.2	NP_071451.2	Q9BYX4-1
IFIH1	XM_047445407.1 linkuse as main transcript	c.329A>G	p.Lys110Arg	missense_variant	4/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 linkuse as main transcript	c.1046A>G	p.Lys349Arg	missense_variant	5/16		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00315

AC:

790

AN:

250826

Hom.:

AF XY:

0.00429

AC XY:

581

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0187

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00264

AC:

3856

AN:

1460620

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

2340

AN XY:

726652

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0198

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00171

Gnomad4 OTH exome

AF:

0.00264

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

152054

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0213

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00158

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00353

AC:

429

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00186

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

IFIH1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

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

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

T;T;.

Eigen

Benign

0.014

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.74

.;T;T

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.43

N;N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.88

.;N;.

REVEL

Benign

0.039

Sift

Benign

0.32

.;T;.

Sift4G

Benign

0.44

.;T;.

Polyphen

0.34

B;B;.

Vest4

0.19

MVP

0.71

MPC

0.024

ClinPred

0.019

GERP RS

6.0

Varity_R

0.15

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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