rs118203557
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000368.5(TSC1):c.1680_1702del(p.Ser561ArgfsTer19) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G560G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
TSC1
NM_000368.5 frameshift
NM_000368.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.69
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 9-132905875-CCCGCAGGGCTTTCATCAGCACTG-C is Pathogenic according to our data. Variant chr9-132905875-CCCGCAGGGCTTTCATCAGCACTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 64763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905875-CCCGCAGGGCTTTCATCAGCACTG-C is described in Lovd as [Pathogenic]. Variant chr9-132905875-CCCGCAGGGCTTTCATCAGCACTG-C is described in Lovd as [Pathogenic]. Variant chr9-132905875-CCCGCAGGGCTTTCATCAGCACTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.1680_1702del | p.Ser561ArgfsTer19 | frameshift_variant | 15/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.1680_1702del | p.Ser561ArgfsTer19 | frameshift_variant | 15/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 04, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 29, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 64763). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser561Argfs*19) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. - |
Tuberous sclerosis syndrome Other:2
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 12, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at