rs35337543

chr2-162279995-C-Gchr2-162279995-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_Moderate PP3_Strong BS2

The NM_022168.4(IFIH1):c.1641+1G>C variant causes a splice donor 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. 2/2 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:4 O:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03768681 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.1641+1G>C		splice_donor_variant		ENST00000649979.2
IFIH1	XM_047445407.1	c.924+1G>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.1641+1G>C		splice_donor_variant			NM_022168.4	P1

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

GnomAD3 exomes AF: 0.00679 AC: 1697 AN: 249994 Hom.: 7 AF XY: 0.00683 AC XY: 923 AN XY: 135116

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 SAS exome AF: 0.000525

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

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00984

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000571

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00969

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

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0138

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 14, 2021	IFIH1 NM_022168.3 intron 8 c.1641+1G>C: This variant has not been reported in the literature in association with traditional Mendelian disease, but has been reported as heterozygous in 3 healthy children who were hospitalized due to viral infection (Asgari 2017 PMID:28716935). This variant is present in 1% (745/67940) of European alleles, including 4 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-19193983-A-T?dataset=gnomad_r3. This variant is present in ClinVar (Variation ID:261563) with at least 2 labs classifying this variant as Benign. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. However, there is limited evidence for this gene and to support loss of function (LOF) as a known disease mechanism. In vitro functional studies suggest that this variant will impact the protein by causing an in-frame loss of 39 amino acids and the skipping of exon 8; thus potentially disrupting signaling function, enzymatic activity and protein stability (Asgari 2017 PMID:28716935). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, flagged submission	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -

not provided Pathogenic:1 Benign:1

Likely pathogenic, flagged submission	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	IFIH1: BS1, BS2 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The IFIH1 c.1641+1G>C variant was identified in the literature found to be associated with Type 1 Diabetes in a large case-control study (Nejentsev_2009_PMID:19264985). The variant was identified in dbSNP (ID: rs35337543), LOVD 3.0 (classified as likely benign and a VUS) and ClinVar (classified as benign by Prevention Genetics and Invitae, as uncertain significance by Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago and as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was not identified in other databases. The variant was identified in control databases in 1888 of 281368 chromosomes (7 homozygous) at a frequency of 0.00671 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1379 of 128286 chromosomes (freq: 0.01075), Latino in 332 of 35158 chromosomes (freq: 0.009443), Other in 66 of 7164 chromosomes (freq: 0.009213), African in 70 of 24914 chromosomes (freq: 0.00281), Ashkenazi Jewish in 13 of 10352 chromosomes (freq: 0.001256), South Asian in 16 of 30490 chromosomes (freq: 0.000525), European (Finnish) in 11 of 25070 chromosomes (freq: 0.000439), and East Asian in 1 of 19934 chromosomes (freq: 0.00005). The c.1641+1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Further, functional analysis of IFIH1 RNA has demonstrated aberrant splicing of the IFIH1 transcript with the c.1641+1G>C variant (Downes_2010_PMID:20844740). However, exon skipping due to loss of the splice consensus sequence is predicted to preserve the reading frame. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Susceptibility to severe COVID-19 Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 01, 2022

- -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 13, 2022

IFIH1 NM_022168.3 exon 8 c.1641+1G>C: This variant has not been reported in the literature in association with traditional Mendelian disease, but has been reported as heterozygous in 3 healthy children who were hospitalized due to viral infection (Asgari 2017 PMID:28716935). This variant is present in 1% (1362/125804) of European alleles, including 7 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-163136505-C-G). This variant is present in ClinVar (Variation ID:261563) with at least 2 labs classifying this variant as Benign. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. However, there is limited evidence for this gene and to support loss of function (LOF) as a known disease mechanism. In vitro functional studies suggest that this variant will impact the protein by causing an in-frame loss of 39 amino acids and the skipping of exon 8; thus potentially disrupting signaling function, enzymatic activity and protein stability (Asgari 2017 PMID:28716935). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Multisystem inflammatory syndrome in children Other:1

risk factor, flagged submission

research

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Nov 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D;D
GERP RS		5.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs35337543; hg19: chr2-163136505; COSMIC: COSV99719009;