rs35593170
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000368.5(TSC1):c.3324C>T(p.Gly1108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,196 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0073 ( 48 hom., cov: 32)
Exomes 𝑓: 0.0042 ( 391 hom. )
Consequence
TSC1
NM_000368.5 synonymous
NM_000368.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0670
Genes affected
TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
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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=-0.82).
BP6
?
Variant 9-132896406-G-A is Benign according to our data. Variant chr9-132896406-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 49024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896406-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.067 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.3324C>T | p.Gly1108= | synonymous_variant | 23/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.3324C>T | p.Gly1108= | synonymous_variant | 23/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00729 AC: 1109AN: 152186Hom.: 49 Cov.: 32
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GnomAD3 exomes AF: 0.0184 AC: 4618AN: 251428Hom.: 323 AF XY: 0.0143 AC XY: 1940AN XY: 135896
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GnomAD4 exome AF: 0.00421 AC: 6156AN: 1461892Hom.: 391 Cov.: 31 AF XY: 0.00368 AC XY: 2674AN XY: 727246
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GnomAD4 genome ? AF: 0.00729 AC: 1110AN: 152304Hom.: 48 Cov.: 32 AF XY: 0.00855 AC XY: 637AN XY: 74468
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:20Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:9
Benign, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Jul 15, 2024 | This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 19. Only high quality variants are reported. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 16, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 22, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 16, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Tuberous sclerosis 1 Benign:6
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University | Jul 10, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 17, 2022 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2016 | Variant summary: The TSC1 c.3324C>T (p.Gly1108Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict the variant to result in the creation of a cyrpitc splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1690/121388 control chromosomes (132 homozygotes), predominantly observed in the Latino subpopulation at a frequency of 0.1302506 (1507/11570). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), strong evidence that this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2023 | - - |
Tuberous sclerosis syndrome Benign:1Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Isolated focal cortical dysplasia type II Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Malignant tumor of urinary bladder Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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