rs4664463

Variant names:

• chr2-162293455-T-C
• rs4664463
• NM_022168.4:c.874+109A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_022168.4(IFIH1):​c.874+109A>G variant causes a intron change. The variant allele was found at a frequency of 0.071 in 631,002 control chromosomes in the GnomAD database, including 6,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (4254 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2378 hom.)
• Consequence: IFIH1 NM_022168.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.75
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, Illumina
• IFIH1-related type 1 interferonopathy

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-162293455-T-C is Benign according to our data. Variant chr2-162293455-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 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.874+109A>G		intron	N/A	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.874+109A>G		intron	N/A	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.874+109A>G		intron	N/A	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.562+109A>G		intron	N/A	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.152 AC: 22994 AN: 151750 Hom.: 4212 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.0452 AC: 21663 AN: 479132 Hom.: 2378 AF XY: 0.0411 AC XY: 10418 AN XY: 253272

African (AFR) AF: 0.412 AC: 5216 AN: 12672

American (AMR) AF: 0.301 AC: 5236 AN: 17388

Ashkenazi Jewish (ASJ) AF: 0.00845 AC: 115 AN: 13604

East Asian (EAS) AF: 0.127 AC: 4037 AN: 31750

South Asian (SAS) AF: 0.0204 AC: 872 AN: 42674

European-Finnish (FIN) AF: 0.0153 AC: 596 AN: 38994

Middle Eastern (MID) AF: 0.0130 AC: 46 AN: 3546

European-Non Finnish (NFE) AF: 0.0131 AC: 3834 AN: 292094

Other (OTH) AF: 0.0648 AC: 1711 AN: 26410

GnomAD4 genome AF: 0.152 AC: 23112 AN: 151870 Hom.: 4254 Cov.: 32 AF XY: 0.152 AC XY: 11263 AN XY: 74254

African (AFR) AF: 0.417 AC: 17266 AN: 41410

American (AMR) AF: 0.251 AC: 3822 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3466

East Asian (EAS) AF: 0.111 AC: 570 AN: 5144

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4828

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 888 AN: 67890

Other (OTH) AF: 0.137 AC: 288 AN: 2108

Alfa AF: 0.117 Hom.: 376

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.85
PhyloP100		3.7
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs4664463; hg19: chr2-163149965;