rs13023380

chr2-162297853-G-Achr2-162297853-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022168.4(IFIH1):c.770-4185C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 151,836 control chromosomes in the GnomAD database, including 12,143 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (12143 hom., cov: 31)
• Consequence: IFIH1 NM_022168.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.770-4185C>T		intron_variant		ENST00000649979.2
IFIH1	XM_047445407.1	c.53-4185C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.770-4185C>T		intron_variant			NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53448 AN: 151718 Hom.: 12146 Cov.: 31

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.00774

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.352 AC: 53435 AN: 151836 Hom.: 12143 Cov.: 31 AF XY: 0.346 AC XY: 25687 AN XY: 74210

Gnomad4 AFR AF: 0.0972

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.00775

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.426

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.385

Alfa AF: 0.474 Hom.: 23110

Bravo AF: 0.332

Asia WGS AF: 0.165 AC: 575 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	9.2
Dann	Benign	0.80

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: rs13023380; hg19: chr2-163154363; COSMIC: COSV55129728;