rs148931779
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_000368.5(TSC1):c.3125G>T(p.Ser1042Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,544 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
TSC1
NM_000368.5 missense
NM_000368.5 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 3.48
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 Likely_benign. Variant got -6 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
BP4
Computational evidence support a benign effect (MetaRNN=0.16519216).
BP6
Variant 9-132896605-C-A is Benign according to our data. Variant chr9-132896605-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207640.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAd4 at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.3125G>T | p.Ser1042Ile | missense_variant | 23/23 | ENST00000298552.9 | NP_000359.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.3125G>T | p.Ser1042Ile | missense_variant | 23/23 | 1 | NM_000368.5 | ENSP00000298552.3 | ||
TSC1 | ENST00000490179.4 | c.3125G>T | p.Ser1042Ile | missense_variant | 24/24 | 3 | ENSP00000495533.2 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249588Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135198
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GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461282Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726874
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GnomAD4 genome AF: 0.000105 AC: 16AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Benign:3
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 15, 2024 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 24, 2017 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2018 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;.;T;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;.;.;.;D;D;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;M;.;.;M;.;M;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;.;.;.;.;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;D;D;.;.;.;.;.;.;.;.
Polyphen
D;.;D;.;.;D;.;D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at