NM_022168.4:c.436A>G

Variant names:

• chr2-162317872-T-C
• rs146721166
• NM_022168.4:c.436A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022168.4(IFIH1):​c.436A>G​(p.Ile146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,586,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I146T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.33
• 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: Labcorp Genetics (formerly Invitae), G2P, Illumina
• IFIH1-related type 1 interferonopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Singleton-Merten syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 (MetaRNN=0.0035294592).
• BP6: Variant 2-162317872-T-C is Benign according to our data. Variant chr2-162317872-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 541790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0012 (183/152310) while in subpopulation AFR AF = 0.00414 (172/41566). AF 95% confidence interval is 0.00363. There are 2 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.436A>G	p.Ile146Val	missense	Exon 1 of 16	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.436A>G	p.Ile146Val	missense	Exon 1 of 16	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000421365.2	TSL:1	c.436A>G	p.Ile146Val	missense	Exon 1 of 2	ENSP00000408450.2	Q9BYX4-2
	IFIH1	ENST00000648433.1		c.436A>G	p.Ile146Val	missense	Exon 1 of 15	ENSP00000496816.1	A0A3B3IRK8

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000299 AC: 68 AN: 227700 AF XY: 0.000221

Gnomad AFR exome AF: 0.00414

Gnomad AMR exome AF: 0.0000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 152 AN: 1433892 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 67 AN XY: 711092

African (AFR) AF: 0.00416 AC: 135 AN: 32456

American (AMR) AF: 0.000123 AC: 5 AN: 40508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 81688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098898

Other (OTH) AF: 0.000152 AC: 9 AN: 59056

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74478

African (AFR) AF: 0.00414 AC: 172 AN: 41566

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.00145

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (1)
-	-	1	IFIH1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.24
DANN	Benign	0.60
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		-1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.010
Sift	Benign	0.28	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.061
MVP		0.14
MPC		0.023
ClinPred		0.014	T
GERP RS		-11
PromoterAI		-0.048	Neutral
Varity_R		0.026
gMVP		0.13
Mutation Taster		=89/11	polymorphism

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: rs146721166; hg19: chr2-163174382;