chr9-132911522-TAAC-T
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBP6
The NM_000368.5(TSC1):c.957_959delGTT(p.Leu320del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
TSC1
NM_000368.5 disruptive_inframe_deletion
NM_000368.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.47
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 0 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_000368.5. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 9-132911522-TAAC-T is Benign according to our data. Variant chr9-132911522-TAAC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411287.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.957_959delGTT | p.Leu320del | disruptive_inframe_deletion | 10/23 | ENST00000298552.9 | NP_000359.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.957_959delGTT | p.Leu320del | disruptive_inframe_deletion | 10/23 | 1 | NM_000368.5 | ENSP00000298552.3 | ||
TSC1 | ENST00000490179.4 | c.957_959delGTT | p.Leu320del | disruptive_inframe_deletion | 11/24 | 3 | ENSP00000495533.2 |
Frequencies
GnomAD3 genomes AF: 0.0000200 AC: 3AN: 149860Hom.: 0 Cov.: 29
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461830Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727226
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GnomAD4 genome AF: 0.0000200 AC: 3AN: 149860Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 72904
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2022 | The c.957_959delGTT variant (also known as p.L320del) is located in coding exon 8 of the TSC1 gene. This variant results from an in-frame GTT deletion at nucleotide positions 957 to 959. This results in the in-frame deletion of a leucine at codon 320. This nucleotide region is not 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. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2019 | The TSC1 c.957_959delGTT; p.Leu320del variant (rs755655903), also known as 954_956GTT[1], is reported in ClinVar (Variation ID: 411287). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single leucine residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of this variant is uncertain at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2023 | See Variant Classification Assertion Criteria. - |
Seizure Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 11, 2017 | - - |
Tuberous sclerosis 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at