rs767455
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001065.4(TNFRSF1A):c.36A>G(p.Pro12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,612 control chromosomes in the GnomAD database, including 135,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.39 ( 12088 hom., cov: 33)
Exomes 𝑓: 0.41 ( 123613 hom. )
Consequence
TNFRSF1A
NM_001065.4 synonymous
NM_001065.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.107
Genes affected
TNFRSF1A (HGNC:11916): (TNF receptor superfamily member 1A) This gene encodes a member of the TNF receptor superfamily of proteins. The encoded receptor is found in membrane-bound and soluble forms that interact with membrane-bound and soluble forms, respectively, of its ligand, tumor necrosis factor alpha. Binding of membrane-bound tumor necrosis factor alpha to the membrane-bound receptor induces receptor trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of the encoded receptor results in release of the soluble form of the receptor, which can interact with free tumor necrosis factor alpha to inhibit inflammation. Mutations in this gene underlie tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by fever, abdominal pain and other features. Mutations in this gene may also be associated with multiple sclerosis in human patients. [provided by RefSeq, Sep 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
?
Variant 12-6341779-T-C is Benign according to our data. Variant chr12-6341779-T-C is described in ClinVar as [Benign]. Clinvar id is 257326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6341779-T-C is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.107 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF1A | NM_001065.4 | c.36A>G | p.Pro12= | synonymous_variant | 1/10 | ENST00000162749.7 | |
TNFRSF1A | NM_001346091.2 | c.-135A>G | 5_prime_UTR_variant | 1/9 | |||
TNFRSF1A | NM_001346092.2 | c.-542A>G | 5_prime_UTR_variant | 1/11 | |||
TNFRSF1A | NR_144351.2 | n.298A>G | non_coding_transcript_exon_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF1A | ENST00000162749.7 | c.36A>G | p.Pro12= | synonymous_variant | 1/10 | 1 | NM_001065.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.393 AC: 59765AN: 152026Hom.: 12096 Cov.: 33
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GnomAD3 exomes AF: 0.374 AC: 93640AN: 250294Hom.: 18566 AF XY: 0.374 AC XY: 50626AN XY: 135412
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GnomAD4 exome AF: 0.406 AC: 593442AN: 1461468Hom.: 123613 Cov.: 46 AF XY: 0.404 AC XY: 293957AN XY: 727038
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GnomAD4 genome ? AF: 0.393 AC: 59763AN: 152144Hom.: 12088 Cov.: 33 AF XY: 0.391 AC XY: 29083AN XY: 74394
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ClinVar
Significance: Benign
Submissions summary: Uncertain:3Benign:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | 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 - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Nov 12, 2023 | This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Benign:2Other:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
TNF receptor-associated periodic fever syndrome (TRAPS) Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Associated with severe COVID-19 disease Uncertain:1
Uncertain significance, no assertion criteria provided | research | HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas | Jul 01, 2023 | - - |
Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1
Uncertain significance, no assertion criteria provided | research | HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas | Feb 09, 2021 | - - |
Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR7 Uncertain:1
Uncertain significance, no assertion criteria provided | research | HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas | Aug 07, 2021 | NA - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at