Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_000368.5(TSC1):c.3195G>A(p.Thr1065=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1065T) 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]
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 9-132896535-C-T is Benign according to our data. Variant chr9-132896535-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 49016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896535-C-T is described in Lovd as [Benign]. Variant chr9-132896535-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-3.68 with no splicing effect.
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Nov 03, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 17, 2020
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. -
not specified Benign:1
Benign, criteria provided, single submitter
clinical testing
GeneDx
Jul 31, 2014
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 syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Nov 30, 2023
- -
TSC1-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Apr 11, 2023
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -