chr2-162272373-G-A

Variant names:

• chr2-162272373-G-A
• rs13418718
• NM_022168.4:c.2469C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022168.4(IFIH1):​c.2469C>T​(p.Ala823Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,612,536 control chromosomes in the GnomAD database, including 4,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (2276 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (1965 hom.)
• Consequence: IFIH1 NM_022168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.963
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-162272373-G-A is Benign according to our data. Variant chr2-162272373-G-A is described in ClinVar as Benign. ClinVar VariationId is 474951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.963 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2469C>T	p.Ala823Ala	synonymous	Exon 13 of 16	NP_071451.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2469C>T	p.Ala823Ala	synonymous	Exon 13 of 16	ENSP00000497271.1
	IFIH1	ENST00000648433.1		c.2352C>T	p.Ala784Ala	synonymous	Exon 12 of 15	ENSP00000496816.1
	IFIH1	ENST00000679938.1		c.2157C>T	p.Ala719Ala	synonymous	Exon 12 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 14184 AN: 151982 Hom.: 2247 Cov.: 32

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: 0.0714

GnomAD2 exomes AF: 0.0243 AC: 6074 AN: 250030 AF XY: 0.0179

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000680

Gnomad OTH exome AF: 0.00921

GnomAD4 exome AF: 0.00933 AC: 13619 AN: 1460436 Hom.: 1965 Cov.: 32 AF XY: 0.00799 AC XY: 5802 AN XY: 726530

African (AFR) AF: 0.332 AC: 11099 AN: 33386

American (AMR) AF: 0.0173 AC: 767 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26092

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.000766 AC: 66 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00921 AC: 53 AN: 5756

European-Non Finnish (NFE) AF: 0.000278 AC: 309 AN: 1111294

Other (OTH) AF: 0.0211 AC: 1276 AN: 60336

GnomAD4 genome AF: 0.0938 AC: 14270 AN: 152100 Hom.: 2276 Cov.: 32 AF XY: 0.0919 AC XY: 6836 AN XY: 74364

African (AFR) AF: 0.326 AC: 13513 AN: 41436

American (AMR) AF: 0.0355 AC: 543 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 67994

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0414 Hom.: 790

Bravo AF: 0.108

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.000710

EpiControl AF: 0.000890

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.8
DANN	Benign	0.71
PhyloP100		0.96
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: rs13418718; hg19: chr2-163128883;