rs774900322
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000368.5(TSC1):c.47C>T(p.Ser16Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S16C) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
TSC1
NM_000368.5 missense
NM_000368.5 missense
Scores
9
8
1
Clinical Significance
Conservation
PhyloP100: 6.68
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TSC1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.903
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.47C>T | p.Ser16Phe | missense_variant | 3/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.47C>T | p.Ser16Phe | missense_variant | 3/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function. ClinVar contains an entry for this variant (Variation ID: 534473). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 16 of the TSC1 protein (p.Ser16Phe). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 16, 2023 | This missense variant replaces serine with phenylalanine at codon 16 of the TSC1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2019 | The p.S16F variant (also known as c.47C>T), located in coding exon 1 of the TSC1 gene, results from a C to T substitution at nucleotide position 47. The serine at codon 16 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.;M;.;M;.;.;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Sift4G
Pathogenic
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen
D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.;.
Vest4
MutPred
Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);Gain of catalytic residue at S16 (P = 0.1209);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at