rs35337543

Variant names:

• chr2-162279995-C-G
• rs35337543
• NM_022168.4:c.1641+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-162279995-C-G
• chr2-162279995-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_022168.4(IFIH1):​c.1641+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0108 in 1,511,626 control chromosomes in the GnomAD database, including 122 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0072 (5 hom., cov: 33)
  • Exomes 𝑓: 0.011 (117 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 U:6 B:5 O:1
• Conservation: PhyloP100: 5.79
• Publications: 54 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 -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.038011696 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 2-162279995-C-G is Benign according to our data. Variant chr2-162279995-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261563.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00724 (1102/152134) while in subpopulation AMR AF = 0.0117 (179/15258). AF 95% confidence interval is 0.0103. There are 5 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1641+1G>C		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.1641+1G>C		splice_donor intron	N/A	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.1524+1333G>C		intron	N/A	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.1329+1G>C		splice_donor intron	N/A	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.00725 AC: 1102 AN: 152016 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00679 AC: 1697 AN: 249994 AF XY: 0.00683

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00941

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0112 AC: 15182 AN: 1359492 Hom.: 117 Cov.: 23 AF XY: 0.0109 AC XY: 7442 AN XY: 682134

African (AFR) AF: 0.00183 AC: 57 AN: 31220

American (AMR) AF: 0.00984 AC: 437 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 33 AN: 25490

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39182

South Asian (SAS) AF: 0.000571 AC: 48 AN: 84088

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53296

Middle Eastern (MID) AF: 0.0134 AC: 74 AN: 5536

European-Non Finnish (NFE) AF: 0.0137 AC: 13965 AN: 1019520

Other (OTH) AF: 0.00969 AC: 550 AN: 56772

GnomAD4 genome AF: 0.00724 AC: 1102 AN: 152134 Hom.: 5 Cov.: 33 AF XY: 0.00696 AC XY: 518 AN XY: 74374

African (AFR) AF: 0.00279 AC: 116 AN: 41550

American (AMR) AF: 0.0117 AC: 179 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 745 AN: 67932

Other (OTH) AF: 0.0138 AC: 29 AN: 2108

Alfa AF: 0.0109 Hom.: 8

Bravo AF: 0.00799

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00648 AC: 787

Asia WGS AF: 0.00145 AC: 6 AN: 3474

EpiCase AF: 0.0120

EpiControl AF: 0.0136

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	1	not provided (3)
-	-	3	not specified (3)
-	1	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (2)
-	2	-	Immunodeficiency 95 (2)
-	1	-	Aicardi-Goutieres syndrome 7 (1)
-	1	-	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 (1)
-	-	-	Multisystem inflammatory syndrome in children (1)
-	-	-	Susceptibility to severe COVID-19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.8
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
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: rs35337543; hg19: chr2-163136505; COSMIC: COSV99719009;