rs12479125

chr2-162302567-T-C

Variant summary

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

The NM_022168.4(IFIH1):c.769+4142A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 152,294 control chromosomes in the GnomAD database, including 441 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 0.034 (441 hom., cov: 33)
• Consequence: IFIH1 NM_022168.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.769+4142A>G		intron_variant		ENST00000649979.2
IFIH1	XM_047445407.1	c.52+4142A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.769+4142A>G		intron_variant			NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5214 AN: 152176 Hom.: 428 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0449

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

GnomAD4 genome AF: 0.0344 AC: 5245 AN: 152294 Hom.: 441 Cov.: 33 AF XY: 0.0370 AC XY: 2756 AN XY: 74460

Gnomad4 AFR AF: 0.00695

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0499 Hom.: 134

Bravo AF: 0.0521

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.4
Dann	Benign	0.66

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: rs12479125; hg19: chr2-163159077;