ClinVar Genomic variation as it relates to human health
NM_022168.4(IFIH1):c.1641+1G>C
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(3); Benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022168.4(IFIH1):c.1641+1G>C
Variation ID: 261563 Accession: VCV000261563.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.2 2: 162279995 (GRCh38) [ NCBI UCSC ] 2: 163136505 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 3, 2016 Aug 4, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022168.4:c.1641+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000002.12:g.162279995C>G NC_000002.11:g.163136505C>G NG_011495.1:g.43535G>C LRG_1235:g.43535G>C LRG_1235t1:c.1641+1G>C - Protein change
- Other names
- -
- Canonical SPDI
- NC_000002.12:162279994:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00559 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00559
1000 Genomes Project 30x 0.00640
The Genome Aggregation Database (gnomAD) 0.00728
Trans-Omics for Precision Medicine (TOPMed) 0.00799
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00815
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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IFIH1 | - | - |
GRCh38 GRCh37 |
1405 | 1432 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (2) |
criteria provided, single submitter
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- | RCV000245122.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000545421.23 | |
Benign (2) |
criteria provided, single submitter
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Jul 1, 2024 | RCV000584843.20 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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- | RCV001778865.6 | |
Susceptibility to severe COVID-19
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Likely risk allele (1) |
no assertion criteria provided
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Jul 1, 2022 | RCV003114429.5 |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV004555860.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2022 | RCV003224242.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000314018.1
First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016 |
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Uncertain significance
(Jun 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 7
Singleton-Merten syndrome 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898745.2
First in ClinVar: Apr 25, 2019 Last updated: Apr 08, 2022 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Oct 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 95
Aicardi-Goutieres syndrome 7 Singleton-Merten syndrome 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920049.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
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 … (more)
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. (less)
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 7
Singleton-Merten syndrome 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000655023.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
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Uncertain significance
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 95
Affected status: unknown
Allele origin:
germline
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Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005045048.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
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., … (more)
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. (less)
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Benign
(Jul 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000693003.15
First in ClinVar: Mar 03, 2018 Last updated: Aug 04, 2024 |
Comment:
IFIH1: BS1, BS2
Number of individuals with the variant: 15
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549363.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Likely risk allele
(Jul 01, 2022)
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no assertion criteria provided
Method: research
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Susceptibility to severe COVID-19
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV003798464.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
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Uncertain significance
(Oct 04, 2020)
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Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV001448260 appears to be redundant with SCV003798464.
(less)
Notes: SCV001448260 appears to
(...more)
Source: NCBI
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Aicardi-Goutieres syndrome 7
Singleton-Merten syndrome 1
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001448260.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Sex: male
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risk factor
(Nov 14, 2021)
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Flagged submission
flagged submission
Method: research
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV002014779 appears to be redundant with SCV003798464.
(less)
Notes: SCV002014779 appears to
(...more)
Source: NCBI
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Multisystem inflammatory syndrome in children
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002014779.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
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Likely pathogenic
(Dec 17, 2022)
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Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV002818173 appears to be redundant with SCV003798464.
(less)
Notes: SCV002818173 appears to
(...more)
Source: NCBI
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818173.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs35337543 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.