chr2-162279995-C-G
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
Consequence
NM_022168.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00725 AC: 1102AN: 152016Hom.: 5 Cov.: 33
GnomAD3 exomes AF: 0.00679 AC: 1697AN: 249994Hom.: 7 AF XY: 0.00683 AC XY: 923AN XY: 135116
GnomAD4 exome AF: 0.0112 AC: 15182AN: 1359492Hom.: 117 Cov.: 23 AF XY: 0.0109 AC XY: 7442AN XY: 682134
GnomAD4 genome AF: 0.00724 AC: 1102AN: 152134Hom.: 5 Cov.: 33 AF XY: 0.00696 AC XY: 518AN XY: 74374
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Benign:1
BS1, BS2, PP3, PS3_supporting -
IFIH1: BS1, BS2 -
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not specified Benign:3
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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. -
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. -
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Uncertain:1Benign:1
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. -
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Susceptibility to severe COVID-19 Pathogenic:1
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Immunodeficiency 95 Uncertain:1
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 Uncertain:1
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Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 Uncertain:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at