rs74162089

Variant names:

• chr2-162267332-G-A
• rs74162089
• NM_022168.4:c.2946C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022168.4(IFIH1):​c.2946C>T​(p.Leu982Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,612,746 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: IFIH1 NM_022168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.209
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-162267332-G-A is Benign according to our data. Variant chr2-162267332-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.209 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00235 (358/152222) while in subpopulation AFR AF = 0.00505 (210/41544). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2946C>T	p.Leu982Leu	synonymous	Exon 16 of 16	NP_071451.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2946C>T	p.Leu982Leu	synonymous	Exon 16 of 16	ENSP00000497271.1
	IFIH1	ENST00000648433.1		c.2829C>T	p.Leu943Leu	synonymous	Exon 15 of 15	ENSP00000496816.1
	IFIH1	ENST00000679938.1		c.2634C>T	p.Leu878Leu	synonymous	Exon 15 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00125 AC: 311 AN: 249646 AF XY: 0.00127

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1460524 Hom.: 8 Cov.: 31 AF XY: 0.00118 AC XY: 854 AN XY: 726398

African (AFR) AF: 0.00530 AC: 177 AN: 33412

American (AMR) AF: 0.00112 AC: 50 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000654 AC: 56 AN: 85608

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53394

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5764

European-Non Finnish (NFE) AF: 0.00112 AC: 1240 AN: 1111700

Other (OTH) AF: 0.00179 AC: 108 AN: 60362

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74444

African (AFR) AF: 0.00505 AC: 210 AN: 41544

American (AMR) AF: 0.00183 AC: 28 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10594

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68000

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00242

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00231

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (1)
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 (1)
-	-	1	IFIH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs74162089; hg19: chr2-163123842;