rs4664463

Positions:

• chr2-162293455-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.874+109A>G		intron_variant		ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.157+109A>G		intron_variant			XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.874+109A>G		intron_variant			NM_022168.4	ENSP00000497271	P1

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

Gnomad4 AFR exome AF: 0.412

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.00845

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0648

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

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.137

Alfa AF: 0.104 Hom.: 307

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.85

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

Other links and lift over

dbSNP: rs4664463; hg19: chr2-163149965;