Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000368.5(TSC1):c.236A>T(p.Tyr79Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y79C) 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]
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000368.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2834985).
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Y79F variant (also known as c.236A>T), located in coding exon 3 of the TSC1 gene, results from an A to T substitution at nucleotide position 236. The tyrosine at codon 79 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);Gain of methylation at K82 (P = 0.1125);