rs2234980
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000368.5(TSC1):βc.3121_3129delβ(p.Ser1041_Ser1043del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000248 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
TSC1
NM_000368.5 inframe_deletion
NM_000368.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.06
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.3121_3129del | p.Ser1041_Ser1043del | inframe_deletion | 23/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.3121_3129del | p.Ser1041_Ser1043del | inframe_deletion | 23/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151998Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000816 AC: 2AN: 245184Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132802
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461346Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726948
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74388
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 13, 2021 | - - |
Tuberous sclerosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 25, 2023 | This variant, c.3121_3129del, results in the deletion of 3 amino acid(s) of the TSC1 protein (p.Ser1041_Ser1043del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759531937, gnomAD 0.0009%). 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: 646728). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2022 | The c.3121_3129delAGCAGCAGC variant (also known as p.S1041_S1043del) is located in coding exon 21 of the TSC1 gene. This variant results from an in-frame AGCAGCAGC deletion at nucleotide positions 3121 to 3129. This results in the in-frame deletion of 3 serine residues at codons 1041 to 1043. These amino acid positions are well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at