rs3747517

Variant names:

• chr2-162272314-T-C
• rs3747517
• NM_022168.4:c.2528A>G
• IFIH1 p.His843Arg

Your query was ambiguous. Multiple possible variants found:

• chr2-162272314-T-C
• chr2-162272314-T-A
• chr2-162272314-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H843C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (35508 hom., cov: 31)
  • Exomes 𝑓: 0.70 (363782 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 4.75
• Publications: 153 publications found

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 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• IFIH1-related type 1 interferonopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Singleton-Merten syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Singleton-Merten dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 95

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2528A>G	p.His843Arg	missense	Exon 13 of 16	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2528A>G	p.His843Arg	missense	Exon 13 of 16	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.2411A>G	p.His804Arg	missense	Exon 12 of 15	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.2216A>G	p.His739Arg	missense	Exon 12 of 15	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102798 AN: 151802 Hom.: 35460 Cov.: 31

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

GnomAD2 exomes AF: 0.678 AC: 169606 AN: 250338 AF XY: 0.673

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 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.: 37 AF XY: 0.698 AC XY: 507034 AN XY: 726516

African (AFR) AF: 0.610 AC: 20401 AN: 33418

American (AMR) AF: 0.813 AC: 36239 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 17860 AN: 26110

East Asian (EAS) AF: 0.344 AC: 13654 AN: 39684

South Asian (SAS) AF: 0.586 AC: 50492 AN: 86188

European-Finnish (FIN) AF: 0.650 AC: 34687 AN: 53348

Middle Eastern (MID) AF: 0.694 AC: 3995 AN: 5754

European-Non Finnish (NFE) AF: 0.725 AC: 805875 AN: 1110846

Other (OTH) AF: 0.681 AC: 41080 AN: 60312

GnomAD4 genome AF: 0.677 AC: 102910 AN: 151918 Hom.: 35508 Cov.: 31 AF XY: 0.671 AC XY: 49846 AN XY: 74250

African (AFR) AF: 0.623 AC: 25792 AN: 41410

American (AMR) AF: 0.776 AC: 11841 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2388 AN: 3472

East Asian (EAS) AF: 0.321 AC: 1653 AN: 5150

South Asian (SAS) AF: 0.573 AC: 2759 AN: 4818

European-Finnish (FIN) AF: 0.633 AC: 6677 AN: 10548

Middle Eastern (MID) AF: 0.743 AC: 217 AN: 292

European-Non Finnish (NFE) AF: 0.728 AC: 49477 AN: 67950

Other (OTH) AF: 0.702 AC: 1484 AN: 2114

Alfa AF: 0.710 Hom.: 192198

Bravo AF: 0.687

Asia WGS AF: 0.475 AC: 1653 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.724

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	2	Singleton-Merten syndrome 1 (2)
-	-	1	Aicardi-Goutieres syndrome 7 (1)
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.55
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.5	N
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	4.2	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.091
gMVP		0.49
Mutation Taster		=97/3	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3747517;

hg19: chr2-163128824;

COSMIC: COSV55127127;