ClinVar Genomic variation as it relates to human health
NM_001065.4(TNFRSF1A):c.625+10A>G
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001065.4(TNFRSF1A):c.625+10A>G
Variation ID: 37038 Accession: VCV000037038.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6330843 (GRCh38) [ NCBI UCSC ] 12: 6440009 (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 1, 2014 Feb 20, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001065.4:c.625+10A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001346091.2:c.301+10A>G intron variant NM_001346092.2:c.166+10A>G intron variant NC_000012.12:g.6330843T>C NC_000012.11:g.6440009T>C NG_007506.1:g.16253A>G LRG_193:g.16253A>G LRG_193t1:c.625+10A>G - Protein change
- Other names
- IVS6, A-G (rs1800693)
- Canonical SPDI
- NC_000012.12:6330842:T:C
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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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0.29972 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.29972
1000 Genomes Project 30x 0.30497
The Genome Aggregation Database (gnomAD), exomes 0.36092
Exome Aggregation Consortium (ExAC) 0.36212
Trans-Omics for Precision Medicine (TOPMed) 0.36778
The Genome Aggregation Database (gnomAD) 0.38055
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.38759
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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TNFRSF1A | - | - |
GRCh38 GRCh37 |
518 | 588 |
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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risk factor (1) |
no assertion criteria provided
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Aug 23, 2012 | RCV000030698.13 | |
Benign (5) |
criteria provided, multiple submitters, no conflicts
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Nov 12, 2023 | RCV000244183.23 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000338370.19 | |
Uncertain significance (1) |
no assertion criteria provided
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Feb 9, 2021 | RCV001354058.9 | |
Uncertain significance (1) |
no assertion criteria provided
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Aug 7, 2021 | RCV001836715.9 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2023 | RCV001618221.22 | |
Benign (1) |
criteria provided, single submitter
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Jan 14, 2022 | RCV002262595.10 | |
Uncertain significance (1) |
no assertion criteria provided
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Jul 1, 2023 | RCV003398577.1 |
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: SCV000306335.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Mar 28, 2016)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540559.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, one paper claims association with MS (less)
Method: Genome/Exome Filtration
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Benign
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000380679.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Mar 03, 2015)
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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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GeneDx
Accession: SCV001846747.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 24174586, 22801493, 23624563)
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Benign
(Jan 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543107.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Benign
(Nov 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Accession: SCV004102054.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary … (more)
This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 53. Only high quality variants are reported. (less)
Number of individuals with the variant: 53
Age: <18 years
Sex: mixed
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001720366.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024 |
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Benign
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605406.9
First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024 |
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risk factor
(Aug 23, 2012)
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no assertion criteria provided
Method: literature only
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MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053359.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2014 |
Comment on evidence:
Gregory et al. (2012) investigated the contribution of the single-nucleotide polymorphism (SNP) rs1800693 to susceptibility to multiple sclerosis associated with the TNFRSF1A region (MS5; 614810). … (more)
Gregory et al. (2012) investigated the contribution of the single-nucleotide polymorphism (SNP) rs1800693 to susceptibility to multiple sclerosis associated with the TNFRSF1A region (MS5; 614810). The SNP rs1800693 is proximal to the TNFRSF1A exon 6/intron 6 boundary, and the G risk allele resulted in skipping of exon 6 in minigene splicing assays. In primary human immune cells, the presence of the risk allele correlated with increased expression of transcripts lacking exon 6. TNFR1 exon 6 skipping results in a frameshift and a premature stop codon, which translates into a protein comprising only the amino-terminal 183 amino acids of TNFR1 followed by a novel 45 amino acid sequence, as confirmed by tandem mass spectrometry. This mutant protein, delta-6-TNFR1, lacks the extracellular carboxy-terminal portion of the fourth cysteine-rich domain of the select protein, the transmembrane domain, and the intracellular region that is essential for appropriate subcellular localization. The mutant protein demonstrated a more diffuse intracellular distribution than the normal localization to the Golgi apparatus. Gregory et al. (2012) found no significant spontaneous NF-kappa-B (see 164011) signaling or TNFR1-mediated apoptosis upon delta-6-TNFR1 expression. However, the mutant protein could potentially retain some intracellular activity by accumulating in the endoplasmic reticulum and evoking a stress response. Gregory et al. (2012) concluded that the combined genetic and functional analyses strongly implicated rs1800693 as the causal SNP in the MS-associated TNFRSF1A region. Because the delta-6-TNFR1 protein is soluble and capable of TNF antagonism, Gregory et al. (2012) concluded that their evidence was consistent with the reported worsening of MS upon anti-TNF therapy. (less)
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Uncertain significance
(Feb 09, 2021)
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no assertion criteria provided
Method: research
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Susceptibility to severe coronavirus disease (COVID-19)
Affected status: yes
Allele origin:
germline
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HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
Accession: SCV001548222.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
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Uncertain significance
(Aug 07, 2021)
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no assertion criteria provided
Method: research
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Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR6
Affected status: yes
Allele origin:
germline
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HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
Accession: SCV001792248.1
First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Comment:
NA
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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:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931384.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(Jul 01, 2023)
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no assertion criteria provided
Method: research
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Associated with severe COVID-19 disease
Affected status: yes
Allele origin:
germline
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HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
Accession: SCV004102847.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
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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:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740646.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074811.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less)
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-04-27
Testing laboratory interpretation: Benign
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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
HelpTitle | Author | Journal | Year | Link |
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Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. | Gregory AP | Nature | 2012 | PMID: 22801493 |
Text-mined citations for rs1800693 ...
HelpRecord last updated May 01, 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.