rs118203379
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate
The NM_000368.5(TSC1):c.381_383del(p.Val128del) variant causes a inframe deletion 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V127V) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
TSC1
NM_000368.5 inframe_deletion
NM_000368.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.70
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_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_000368.5
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000368.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 9-132923472-GACA-G is Pathogenic according to our data. Variant chr9-132923472-GACA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49038.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132923472-GACA-G is described in Lovd as [Pathogenic]. Variant chr9-132923472-GACA-G is described in Lovd as [Pathogenic]. Variant chr9-132923472-GACA-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.381_383del | p.Val128del | inframe_deletion | 6/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.381_383del | p.Val128del | inframe_deletion | 6/23 | 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: Likely pathogenic
Submissions summary: Pathogenic:1Other:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
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) | - | - - |
Tuberous sclerosis 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2022 | Experimental studies have shown that this variant affects TSC1 function (PMID: 21309039). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 49038). This variant is also known as c.379_381delTGT (p.128delV). This variant has been observed in individuals with tuberous sclerosis and/or tuberous sclerosis complex (PMID: 18830229; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.381_383del, results in the deletion of 1 amino acid(s) of the TSC1 protein (p.Val128del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
Splicing
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Calibrated prediction
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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