Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000368.5(TSC1):c.1701G>A(p.Ala567=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,612,272 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A567A) has been classified as Likely benign.
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]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 9-132905877-C-T is Benign according to our data. Variant chr9-132905877-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905877-C-T is described in Lovd as [Benign].
BP7
?
BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.224 with no splicing effect.
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00147 (224/152318) while in subpopulation AFR AF= 0.00488 (203/41560). AF 95% confidence interval is 0.00433. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Genetic Services Laboratory, University of Chicago
Oct 30, 2017
- -
Benign, criteria provided, single submitter
clinical testing
GeneDx
Oct 01, 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jan 15, 2021
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Tuberous sclerosis 1 Benign:4
Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
- -
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
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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
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Jul 07, 2023
- -
not provided Benign:3
Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Aug 22, 2018
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Benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
Aug 22, 2018
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Apr 01, 2024
TSC1: BP4, BP7, BS1 -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 12, 2014
This alteration is classified as likely 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. -
Benign, criteria provided, single submitter
curation
Sema4, Sema4
Oct 20, 2020
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Tuberous sclerosis syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Feb 05, 2024
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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. -