rs118203567
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000368.5(TSC1):āc.1726T>Cā(p.Leu576=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,318 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0023 ( 10 hom., cov: 32)
Exomes š: 0.0014 ( 47 hom. )
Consequence
TSC1
NM_000368.5 synonymous
NM_000368.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.240
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=-0.86).
BP6
?
Variant 9-132905852-A-G is Benign according to our data. Variant chr9-132905852-A-G is described in ClinVar as [Benign]. Clinvar id is 48821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905852-A-G is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-0.24 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00225 (343/152334) while in subpopulation EAS AF= 0.0512 (265/5178). AF 95% confidence interval is 0.0461. There are 10 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 343 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.1726T>C | p.Leu576= | synonymous_variant | 15/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.1726T>C | p.Leu576= | synonymous_variant | 15/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00225 AC: 343AN: 152216Hom.: 10 Cov.: 32
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GnomAD3 exomes AF: 0.00401 AC: 1006AN: 251086Hom.: 28 AF XY: 0.00367 AC XY: 498AN XY: 135694
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GnomAD4 exome AF: 0.00139 AC: 2026AN: 1460984Hom.: 47 Cov.: 31 AF XY: 0.00132 AC XY: 959AN XY: 726638
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GnomAD4 genome ? AF: 0.00225 AC: 343AN: 152334Hom.: 10 Cov.: 32 AF XY: 0.00239 AC XY: 178AN XY: 74498
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ClinVar
Significance: Benign
Submissions summary: Benign:17Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:7
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 13, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 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. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 13, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Tuberous sclerosis 1 Benign:5
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 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 | - - |
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 | Sep 20, 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.1726T>C (p.Leu576Leu) 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, and 5/5 Alamut algorithms predict no significant change to normal splicing. This variant was found in 458/121316 control chromosomes (16 homozygotes) at a frequency of 0.0037753, which is approximately 151 times the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together and based on the synonymous nature of this variant and the high allele frequency in the general population, this variant is classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 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 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 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
Source:
Name
Calibrated prediction
Score
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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