rs6432714

Variant names:

• chr2-162280842-A-T
• rs6432714
• NM_022168.4:c.1524+486T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022168.4(IFIH1):​c.1524+486T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 151,968 control chromosomes in the GnomAD database, including 4,271 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 0.15 (4271 hom., cov: 32)
• Consequence: IFIH1 NM_022168.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.575
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.1524+486T>A		intron_variant	Intron 7 of 15	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.807+486T>A		intron_variant	Intron 6 of 14		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.1524+486T>A		intron_variant	Intron 7 of 15		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23070 AN: 151850 Hom.: 4225 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.153 AC: 23191 AN: 151968 Hom.: 4271 Cov.: 32 AF XY: 0.152 AC XY: 11298 AN XY: 74292

African (AFR) AF: 0.417 AC: 17268 AN: 41444

American (AMR) AF: 0.252 AC: 3833 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.123 AC: 633 AN: 5150

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4820

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0131 AC: 889 AN: 67934

Other (OTH) AF: 0.136 AC: 287 AN: 2110

Alfa AF: 0.0913 Hom.: 320

Bravo AF: 0.188

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.44
PhyloP100		-0.57
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: rs6432714; hg19: chr2-163137352;