rs1990760

Positions:

chr2-162267541-C-T

Variant summary

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

The NM_022168.4(IFIH1):c.2836G>A(p.Ala946Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,609,886 control chromosomes in the GnomAD database, including 262,583 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 Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 18236 hom., cov: 33)

Exomes 𝑓: 0.57 ( 244347 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.750

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=2.7895177E-5).

BP6

Variant 2-162267541-C-T is Benign according to our data. Variant chr2-162267541-C-T is described in ClinVar as [Benign]. Clinvar id is 261566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 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.2836G>A	p.Ala946Thr	missense_variant	15/16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1 linkuse as main transcript	c.2119G>A	p.Ala707Thr	missense_variant	14/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 linkuse as main transcript	c.2836G>A	p.Ala946Thr	missense_variant	15/16		NM_022168.4	ENSP00000497271	P1	Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.452

AC:

68651

AN:

151970

Hom.:

18242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.574

Gnomad AMR

AF:

0.443

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.514

Gnomad FIN

AF:

0.568

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.610

Gnomad OTH

AF:

0.471

GnomAD3 exomes

AF:

0.502

AC:

125999

AN:

251196

Hom.:

34569

AF XY:

0.515

AC XY:

69974

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.424

Gnomad ASJ exome

AF:

0.454

Gnomad EAS exome

AF:

0.174

Gnomad SAS exome

AF:

0.533

Gnomad FIN exome

AF:

0.572

Gnomad NFE exome

AF:

0.606

Gnomad OTH exome

AF:

0.529

GnomAD4 exome

AF:

0.569

AC:

830046

AN:

1457798

Hom.:

244347

Cov.:

AF XY:

0.570

AC XY:

413369

AN XY:

725498

show subpopulations

Gnomad4 AFR exome

AF:

0.166

Gnomad4 AMR exome

AF:

0.426

Gnomad4 ASJ exome

AF:

0.452

Gnomad4 EAS exome

AF:

0.202

Gnomad4 SAS exome

AF:

0.529

Gnomad4 FIN exome

AF:

0.575

Gnomad4 NFE exome

AF:

0.609

Gnomad4 OTH exome

AF:

0.529

GnomAD4 genome

AF:

0.451

AC:

68647

AN:

152088

Hom.:

18236

Cov.:

AF XY:

0.448

AC XY:

33329

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.185

Gnomad4 AMR

AF:

0.442

Gnomad4 ASJ

AF:

0.462

Gnomad4 EAS

AF:

0.195

Gnomad4 SAS

AF:

0.515

Gnomad4 FIN

AF:

0.568

Gnomad4 NFE

AF:

0.610

Gnomad4 OTH

AF:

0.468

Alfa

AF:

0.563

Hom.:

62070

Bravo

AF:

0.424

TwinsUK

AF:

0.598

AC:

2217

ALSPAC

AF:

0.605

AC:

2330

ESP6500AA

AF:

0.185

AC:

816

ESP6500EA

AF:

0.603

AC:

5185

ExAC

AF:

0.505

AC:

61267

Asia WGS

AF:

0.326

AC:

1136

AN:

3478

EpiCase

AF:

0.596

EpiControl

AF:

0.586

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 31866997, 22561518, 28553952, 28973304, 23441136, 27720759, 28000722, 23734776, 16699517, 24386202, 20644636, 20694011, 20467774, 17535987, 19324880, 21705624, 19539001, 18927125, 19841890, 24117221, 24995871) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Singleton-Merten syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.028

T;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.69

.;T;T

MetaRNN

Benign

0.000028

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

0.21

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

0.19

.;N;.

REVEL

Benign

0.036

Sift

Benign

0.51

.;T;.

Sift4G

Benign

0.62

.;T;.

Polyphen

0.10

B;B;.

Vest4

0.017

MPC

0.024

ClinPred

0.0023

GERP RS

3.9

Varity_R

0.075

gMVP

0.23

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