rs3747517

Positions:

chr2-162272314-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_022168.4(IFIH1):c.2528A>G(p.His843Arg) variant causes a missense change. The variant allele was found at a frequency of 0.699 in 1,612,150 control chromosomes in the GnomAD database, including 399,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 35508 hom., cov: 31)

Exomes 𝑓: 0.70 ( 363782 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 4.75

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 -18 ACMG points.

PM1

In a domain Helicase C-terminal (size 182) in uniprot entity IFIH1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022168.4

BP4

Computational evidence support a benign effect (MetaRNN=8.693561E-7).

BP6

Variant 2-162272314-T-C is Benign according to our data. Variant chr2-162272314-T-C is described in ClinVar as [Benign]. Clinvar id is 261565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.765 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.2528A>G	p.His843Arg	missense_variant	13/16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1 linkuse as main transcript	c.1811A>G	p.His604Arg	missense_variant	12/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 linkuse as main transcript	c.2528A>G	p.His843Arg	missense_variant	13/16		NM_022168.4	ENSP00000497271	P1	Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.677

AC:

102798

AN:

151802

Hom.:

35460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.622

Gnomad AMI

AF:

0.684

Gnomad AMR

AF:

0.776

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.321

Gnomad SAS

AF:

0.571

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.742

Gnomad NFE

AF:

0.728

Gnomad OTH

AF:

0.700

GnomAD3 exomes

AF:

0.678

AC:

169606

AN:

250338

Hom.:

59530

AF XY:

0.673

AC XY:

91061

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.622

Gnomad AMR exome

AF:

0.819

Gnomad ASJ exome

AF:

0.685

Gnomad EAS exome

AF:

0.308

Gnomad SAS exome

AF:

0.590

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.731

Gnomad OTH exome

AF:

0.693

GnomAD4 exome

AF:

0.701

AC:

1024283

AN:

1460232

Hom.:

363782

Cov.:

AF XY:

0.698

AC XY:

507034

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.610

Gnomad4 AMR exome

AF:

0.813

Gnomad4 ASJ exome

AF:

0.684

Gnomad4 EAS exome

AF:

0.344

Gnomad4 SAS exome

AF:

0.586

Gnomad4 FIN exome

AF:

0.650

Gnomad4 NFE exome

AF:

0.725

Gnomad4 OTH exome

AF:

0.681

GnomAD4 genome

AF:

0.677

AC:

102910

AN:

151918

Hom.:

35508

Cov.:

AF XY:

0.671

AC XY:

49846

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.623

Gnomad4 AMR

AF:

0.776

Gnomad4 ASJ

AF:

0.688

Gnomad4 EAS

AF:

0.321

Gnomad4 SAS

AF:

0.573

Gnomad4 FIN

AF:

0.633

Gnomad4 NFE

AF:

0.728

Gnomad4 OTH

AF:

0.702

Alfa

AF:

0.713

Hom.:

102301

Bravo

AF:

0.687

TwinsUK

AF:

0.721

AC:

2674

ALSPAC

AF:

0.727

AC:

2800

ESP6500AA

AF:

0.624

AC:

2751

ESP6500EA

AF:

0.726

AC:

6244

ExAC

AF:

0.674

AC:

81812

Asia WGS

AF:

0.475

AC:

1653

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	This variant is associated with the following publications: (PMID: 31866997, 27720759, 17000706, 23535865) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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 92% of patients studied by a panel of primary immunodeficiencies. Number of patients: 88. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Singleton-Merten syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Aicardi-Goutieres syndrome 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

0.035

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.070

T;T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.35

.;T;T

MetaRNN

Benign

8.7e-7

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.5

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

4.2

.;N;.

REVEL

Benign

0.16

Sift

Benign

1.0

.;T;.

Sift4G

Benign

1.0

.;T;.

Polyphen

0.0

B;B;.

Vest4

0.14

MPC

0.027

ClinPred

0.0039

GERP RS

5.8

Varity_R

0.091

gMVP

0.49

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