2-162273887-C-T

Variant names:

• chr2-162273887-C-T
• rs148369169
• NM_022168.4:c.2362G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022168.4(IFIH1):​c.2362G>A​(p.Ala788Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000394 in 1,609,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A788S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.85
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012292206).
• BP6: Variant 2-162273887-C-T is Benign according to our data. Variant chr2-162273887-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541788.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00193 (294/152246) while in subpopulation AFR AF = 0.00642 (267/41562). AF 95% confidence interval is 0.00579. There are 0 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.2362G>A	p.Ala788Thr	missense	Exon 12 of 16	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2362G>A	p.Ala788Thr	missense	Exon 12 of 16	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.2245G>A	p.Ala749Thr	missense	Exon 11 of 15	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.2050G>A	p.Ala684Thr	missense	Exon 11 of 15	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000608 AC: 152 AN: 250062 AF XY: 0.000503

Gnomad AFR exome AF: 0.00685

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000234 AC: 341 AN: 1457422 Hom.: 0 Cov.: 28 AF XY: 0.000221 AC XY: 160 AN XY: 725270

African (AFR) AF: 0.00595 AC: 198 AN: 33298

American (AMR) AF: 0.000764 AC: 34 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26082

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39616

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85880

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53390

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.0000695 AC: 77 AN: 1108692

Other (OTH) AF: 0.000398 AC: 24 AN: 60236

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74426

African (AFR) AF: 0.00642 AC: 267 AN: 41562

American (AMR) AF: 0.00111 AC: 17 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000677 Hom.: 2

Bravo AF: 0.00207

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.000110

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.57
MPC		0.20
ClinPred		0.053	T
GERP RS		4.8
Varity_R		0.82
gMVP		0.85
Mutation Taster		=63/37	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: rs148369169; hg19: chr2-163130397;