2-162281473-T-C

Position:

chr2-162281473-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022168.4(IFIH1):c.1379A>G(p.His460Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0475 in 1,611,932 control chromosomes in the GnomAD database, including 10,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.15 ( 4261 hom., cov: 32)

Exomes 𝑓: 0.037 ( 6458 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.05

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=0.0037111044).

BP6

Variant 2-162281473-T-C is Benign according to our data. Variant chr2-162281473-T-C is described in ClinVar as [Benign]. Clinvar id is 1170345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4 linkuse as main transcript	c.1379A>G	p.His460Arg	missense_variant	7/16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1 linkuse as main transcript	c.662A>G	p.His221Arg	missense_variant	6/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 linkuse as main transcript	c.1379A>G	p.His460Arg	missense_variant	7/16		NM_022168.4	ENSP00000497271	P1	Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23046

AN:

151878

Hom.:

4215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.0248

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.130

GnomAD3 exomes

AF:

0.0967

AC:

24216

AN:

250532

Hom.:

3868

AF XY:

0.0762

AC XY:

10325

AN XY:

135452

show subpopulations

Gnomad AFR exome

AF:

0.427

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.132

Gnomad SAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0619

GnomAD4 exome

AF:

0.0366

AC:

53415

AN:

1459936

Hom.:

6458

Cov.:

AF XY:

0.0334

AC XY:

24280

AN XY:

726314

show subpopulations

Gnomad4 AFR exome

AF:

0.424

Gnomad4 AMR exome

AF:

0.332

Gnomad4 ASJ exome

AF:

0.00783

Gnomad4 EAS exome

AF:

0.139

Gnomad4 SAS exome

AF:

0.0221

Gnomad4 FIN exome

AF:

0.0154

Gnomad4 NFE exome

AF:

0.0114

Gnomad4 OTH exome

AF:

0.0546

GnomAD4 genome

AF:

0.152

AC:

23167

AN:

151996

Hom.:

4261

Cov.:

AF XY:

0.152

AC XY:

11293

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.416

Gnomad4 AMR

AF:

0.251

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.124

Gnomad4 SAS

AF:

0.0247

Gnomad4 FIN

AF:

0.0120

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.136

Alfa

AF:

0.0400

Hom.:

1660

Bravo

AF:

0.188

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.415

AC:

1828

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.0927

AC:

11244

Asia WGS

AF:

0.128

AC:

445

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2021	This variant is associated with the following publications: (PMID: 23441136) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.057

T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.035

.;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.4

N;N;.

MutationTaster

Benign

0.57

P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

2.5

.;N;.

REVEL

Benign

0.11

Sift

Benign

1.0

.;T;.

Sift4G

Benign

1.0

.;T;.

Polyphen

0.0

B;B;.

Vest4

0.051

MPC

0.027

ClinPred

0.0054

GERP RS

5.9

Varity_R

0.18

gMVP

0.59

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