chr2-162267194-C-T

Variant names:

• chr2-162267194-C-T
• rs11891191
• NM_022168.4:c.*6G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022168.4(IFIH1):​c.*6G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,552,720 control chromosomes in the GnomAD database, including 4,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (2270 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (1755 hom.)
• Consequence: IFIH1 NM_022168.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.692
• Publications: 8 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, G2P, Labcorp Genetics (formerly Invitae)
• IFIH1-related type 1 interferonopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-162267194-C-T is Benign according to our data. Variant chr2-162267194-C-T is described in ClinVar as Benign. ClinVar VariationId is 1224812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.*6G>A		3_prime_UTR	Exon 16 of 16	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.*6G>A		3_prime_UTR	Exon 16 of 16	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.*6G>A		3_prime_UTR	Exon 15 of 15	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.*6G>A		3_prime_UTR	Exon 15 of 15	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14187 AN: 152112 Hom.: 2241 Cov.: 33

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0717

GnomAD2 exomes AF: 0.0257 AC: 5459 AN: 212312 AF XY: 0.0189

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000734

Gnomad OTH exome AF: 0.00980

GnomAD4 exome AF: 0.00870 AC: 12181 AN: 1400490 Hom.: 1755 Cov.: 27 AF XY: 0.00764 AC XY: 5309 AN XY: 695266

African (AFR) AF: 0.330 AC: 9973 AN: 30210

American (AMR) AF: 0.0193 AC: 605 AN: 31372

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 43 AN: 23668

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39210

South Asian (SAS) AF: 0.000701 AC: 55 AN: 78478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52330

Middle Eastern (MID) AF: 0.00887 AC: 37 AN: 4170

European-Non Finnish (NFE) AF: 0.000275 AC: 298 AN: 1083284

Other (OTH) AF: 0.0202 AC: 1169 AN: 57768

GnomAD4 genome AF: 0.0938 AC: 14273 AN: 152230 Hom.: 2270 Cov.: 33 AF XY: 0.0918 AC XY: 6831 AN XY: 74440

African (AFR) AF: 0.326 AC: 13515 AN: 41490

American (AMR) AF: 0.0355 AC: 543 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68022

Other (OTH) AF: 0.0710 AC: 150 AN: 2114

Alfa AF: 0.0353 Hom.: 1209

Bravo AF: 0.108

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.18
PhyloP100		-0.69
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: rs11891191; hg19: chr2-163123704;