9-132897563-GT-GTT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000368.5(TSC1):c.2672dupA(p.Asn891LysfsTer13) variant causes a frameshift change involving the alteration of a non-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: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TSC1
NM_000368.5 frameshift
NM_000368.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.75
Publications
4 publications found
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]
TSC1 Gene-Disease associations (from GenCC):
- tuberous sclerosisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- tuberous sclerosis 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
- lung lymphangioleiomyomatosisInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- tuberous sclerosis complexInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 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 9-132897563-G-GT is Pathogenic according to our data. Variant chr9-132897563-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 48989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TSC1 | MANE Select | c.2672dupA | p.Asn891LysfsTer13 | frameshift | Exon 21 of 23 | NP_000359.1 | Q92574-1 | ||
| TSC1 | c.2672dupA | p.Asn891LysfsTer13 | frameshift | Exon 21 of 23 | NP_001393521.1 | X5D9D2 | |||
| TSC1 | c.2672dupA | p.Asn891LysfsTer13 | frameshift | Exon 21 of 23 | NP_001393522.1 | Q92574-1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TSC1 | TSL:1 MANE Select | c.2672dupA | p.Asn891LysfsTer13 | frameshift | Exon 21 of 23 | ENSP00000298552.3 | Q92574-1 | ||
| TSC1 | TSL:3 | c.2672dupA | p.Asn891LysfsTer13 | frameshift | Exon 22 of 24 | ENSP00000495533.2 | Q92574-1 | ||
| TSC1 | c.2672dupA | p.Asn891LysfsTer13 | frameshift | Exon 21 of 23 | ENSP00000495158.1 | Q92574-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD2 exomes AF: 0.00 AC: 0AN: 214594 AF XY: 0.00
GnomAD2 exomes
AF:
AC:
0
AN:
214594
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1179686Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 580490
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1179686
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
580490
African (AFR)
AF:
AC:
0
AN:
24998
American (AMR)
AF:
AC:
0
AN:
32008
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
16794
East Asian (EAS)
AF:
AC:
0
AN:
16420
South Asian (SAS)
AF:
AC:
0
AN:
67456
European-Finnish (FIN)
AF:
AC:
0
AN:
32694
Middle Eastern (MID)
AF:
AC:
0
AN:
4116
European-Non Finnish (NFE)
AF:
AC:
0
AN:
942110
Other (OTH)
AF:
AC:
0
AN:
43090
GnomAD4 genome
GnomAD4 genome
Cov.:
31
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
5
-
-
Tuberous sclerosis 1 (5)
1
-
-
Hereditary cancer-predisposing syndrome (1)
1
-
-
Tuberous sclerosis syndrome (2)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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