rs118203712
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000368.5(TSC1):c.2569del(p.Glu857ArgfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). 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: 7.65
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-132900770-TC-T is Pathogenic according to our data. Variant chr9-132900770-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 48977.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132900770-TC-T is described in Lovd as [Pathogenic]. Variant chr9-132900770-TC-T is described in Lovd as [Pathogenic]. Variant chr9-132900770-TC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.2569del | p.Glu857ArgfsTer21 | frameshift_variant | 20/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.2569del | p.Glu857ArgfsTer21 | frameshift_variant | 20/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2014 | c.2569delG: p.Glu857ArgfsX21 (E857RfsX21) in exon 20 of the TSC1 gene (NM_000368.4). The normal sequence with the base that is deleted in braces is: TGGG{G}AGGT. The c.2569delG mutation in the TSC1 gene has been reported previously in association with TSC (van Slegtenhorst et al., 1999; Sancak et al., 2005). The deletion causes a frameshift starting with codon Glutamic acid 857, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Glu857ArgfsX21. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Other frameshift mutations, including one caused by a duplication at the same position (c.2569dupG), have been reported in association with TSC (Dabora et al., 2001). This result is consistent with a diagnosis of tuberous sclerosis complex. The variant is found in INFANT-EPI panel(s). - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
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Calibrated prediction
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Prediction
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