rs118203529
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000368.5(TSC1):c.1433A>G(p.Glu478Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E478Q) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
TSC1
NM_000368.5 missense
NM_000368.5 missense
Scores
5
12
1
Clinical Significance
Conservation
PhyloP100: 4.78
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TSC1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.1433A>G | p.Glu478Gly | missense_variant | 14/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.1433A>G | p.Glu478Gly | missense_variant | 14/23 | 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
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 478 of the TSC1 protein (p.Glu478Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 48781). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect TSC1 function (PMID: 19747374, 21309039). 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. - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;D;.;.;D;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.;.;M;.;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;D;N;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;D;D;.;.;.;.;.;.;.;.
Polyphen
D;.;D;.;.;D;.;D;.;.;.
Vest4
MutPred
Gain of methylation at K477 (P = 0.166);.;Gain of methylation at K477 (P = 0.166);.;.;Gain of methylation at K477 (P = 0.166);.;Gain of methylation at K477 (P = 0.166);.;Gain of methylation at K477 (P = 0.166);.;
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