2-162268086-C-T

Variant names:

• chr2-162268086-C-T
• rs35732034
• NM_022168.4:c.2807+1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 12P and 9B. PVS1 PS3 BP6 BS1 BS2

The NM_022168.4(IFIH1):​c.2807+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,591,006 control chromosomes in the GnomAD database, including 86 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002818255: PS3".

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (79 hom.)
• Consequence: IFIH1 NM_022168.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:7
• Conservation: PhyloP100: 7.28
• Publications: 41 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002818255: PS3
• BP6: Variant 2-162268086-C-T is Benign according to our data. Variant chr2-162268086-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541779.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00539 (821/152302) while in subpopulation SAS AF = 0.0101 (49/4832). AF 95% confidence interval is 0.00788. There are 7 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD 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.2807+1G>A		splice_donor intron	N/A	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2807+1G>A		splice_donor intron	N/A	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.2690+1G>A		splice_donor intron	N/A	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.2495+1G>A		splice_donor intron	N/A	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 818 AN: 152184 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00790

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00658 AC: 1559 AN: 236838 AF XY: 0.00718

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00221

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00886 AC: 12746 AN: 1438704 Hom.: 79 Cov.: 30 AF XY: 0.00904 AC XY: 6454 AN XY: 714000

African (AFR) AF: 0.00126 AC: 41 AN: 32434

American (AMR) AF: 0.00311 AC: 127 AN: 40834

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 266 AN: 25288

East Asian (EAS) AF: 0.0206 AC: 807 AN: 39234

South Asian (SAS) AF: 0.0118 AC: 958 AN: 81416

European-Finnish (FIN) AF: 0.00202 AC: 107 AN: 53008

Middle Eastern (MID) AF: 0.00707 AC: 40 AN: 5658

European-Non Finnish (NFE) AF: 0.00901 AC: 9928 AN: 1101374

Other (OTH) AF: 0.00794 AC: 472 AN: 59458

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152302 Hom.: 7 Cov.: 33 AF XY: 0.00487 AC XY: 363 AN XY: 74470

African (AFR) AF: 0.00152 AC: 63 AN: 41566

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00792 AC: 41 AN: 5178

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00803 AC: 546 AN: 68020

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.00748 Hom.: 29

Bravo AF: 0.00493

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00682 AC: 828

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
2	-	-	Immunodeficiency 95 (2)
-	-	1	Aicardi-Goutieres syndrome 7 (1)
-	-	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_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.3
GERP RS		4.7
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35732034; hg19: chr2-163124596; COSMIC: COSV99079282;