chr2-162279995-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_ModerateBS1_SupportingBS2

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:2U:5B:5O:1

Conservation

PhyloP100: 5.79

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.1641+1G>C		splice_donor_variant, intron_variant	Intron 8 of 15	ENST00000649979.2	NP_071451.2	Q9BYX4-1
IFIH1	XM_047445407.1 link	c.924+1G>C		splice_donor_variant, intron_variant	Intron 7 of 14		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.1641+1G>C		splice_donor_variant, intron_variant	Intron 8 of 15		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.00725

AC:

1102

AN:

152016

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00683

AC XY:

923

AN XY:

135116

show subpopulations

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.:

AF XY:

0.0109

AC XY:

7442

AN XY:

682134

show subpopulations

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.:

Cov.:

AF XY:

0.00696

AC XY:

518

AN XY:

74374

show subpopulations

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.:

Bravo

AF:

0.00799

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.00648

AC:

787

Asia WGS

AF:

0.00145

AC:

AN:

3474

EpiCase

AF:

0.0120

EpiControl

AF:

0.0136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2024	BS1, BS2, PP3, PS3_supporting -
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	Jan 01, 2025	IFIH1: BS1, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2025	Variant summary: IFIH1 c.1641+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing, however current evidence is not sufficient to establish loss of function as a mechanism for disease. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0068 in 249994 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 7000 fold of the estimated maximal expected allele frequency for a pathogenic variant in IFIH1 causing Singleton-Merten syndrome 1 phenotype (1e-06). To our knowledge, no occurrence of c.1641+1G>C in individuals affected with Singleton-Merten syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 261563). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1

Uncertain:1Benign: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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

Susceptibility to severe COVID-19

Pathogenic:1

Likely risk allele, flagged submission

research

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

Jul 01, 2022

- -

Immunodeficiency 95

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jan 05, 2024

The IFIH1 c.1641+1G>C variant has been reported in three unrelated individuals that required noninvasive ventilatory support for respiratory syncytial virus bronchiolitis (Asgari S et al., PMID: 28716935). This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the eighth exon, leading to an in-frame transcript. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.07% in the European non-Finnish population. This variant has been reported in the ClinVar database as a germline variant of uncertain significance for Immunodeficiency 95 and benign for Aicardi-Goutieres syndrome 7 and Singleton-Merten syndrome 1. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

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. -

Aicardi-Goutieres syndrome 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 04, 2020

- -

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

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over