2-162297853-G-A

Variant names:

• chr2-162297853-G-A
• rs13023380
• NM_022168.4:c.770-4185C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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: PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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 -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 rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.770-4185C>T		intron_variant	Intron 3 of 15	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.53-4185C>T		intron_variant	Intron 2 of 14		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.770-4185C>T		intron_variant	Intron 3 of 15		NM_022168.4	ENSP00000497271.1

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

African (AFR) AF: 0.0972 AC: 4028 AN: 41428

American (AMR) AF: 0.361 AC: 5515 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3472

East Asian (EAS) AF: 0.00775 AC: 40 AN: 5158

South Asian (SAS) AF: 0.348 AC: 1677 AN: 4822

European-Finnish (FIN) AF: 0.426 AC: 4469 AN: 10490

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35097 AN: 67902

Other (OTH) AF: 0.385 AC: 811 AN: 2104

Alfa AF: 0.474 Hom.: 27317

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
PhyloP100		-0.30
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: rs13023380; hg19: chr2-163154363; COSMIC: COSV55129728;