9-132897563-G-GT

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 1.75

Publications

4 publications found

Variant links:

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 sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
lung lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSC1 links:

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC1	NM_000368.5	MANE Select	c.2672dupA	p.Asn891LysfsTer13	frameshift	Exon 21 of 23	NP_000359.1
TSC1	NM_001406592.1		c.2672dupA	p.Asn891LysfsTer13	frameshift	Exon 21 of 23	NP_001393521.1
TSC1	NM_001406593.1		c.2672dupA	p.Asn891LysfsTer13	frameshift	Exon 21 of 23	NP_001393522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2672dupA	p.Asn891LysfsTer13	frameshift	Exon 21 of 23	ENSP00000298552.3
TSC1	ENST00000490179.4	TSL:3	c.2672dupA	p.Asn891LysfsTer13	frameshift	Exon 22 of 24	ENSP00000495533.2
TSC1	ENST00000643875.1		c.2672dupA	p.Asn891LysfsTer13	frameshift	Exon 21 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

214594

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1179686

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

580490

African (AFR)

AF:

0.00

AC:

AN:

24998

American (AMR)

AF:

0.00

AC:

AN:

32008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16794

East Asian (EAS)

AF:

0.00

AC:

AN:

16420

South Asian (SAS)

AF:

0.00

AC:

AN:

67456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

942110

Other (OTH)

AF:

0.00

AC:

AN:

43090

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Pathogenic:5

Oasi Research Institute-IRCCS

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The genomic variant c.2672dupA is a frameshift mutation resulting from the duplication of a single nucleotide.This variant creates a premature translational stop signal and is expected to result in a protein truncation or nonsense-mediated decay. ACMG criteria: PVS1 (LOF), PP4 (phenotype match), PM2 (absent from controls), PP3 (in silico evidence), PS2 (de novo)= Pathogenic. Based on the evidence outlined above, the variant was classified as Pathogenic.

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 observed in individuals affected with tuberous sclerosis complex (PMID: 9328481, 9803264, 9863590, 10363127). This variant is also known as 2887insA and 2887_2888insA in the literature. ClinVar contains an entry for this variant (Variation ID: 48989). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn891Lysfs*13) in the TSC1 gene. It is expected to result in an absent or disrupted protein product.

Jun 09, 2020

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 21, 2024

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21811971, 36232477].

Tuberous sclerosis syndrome

Pathogenic:1Other:1

Tuberous sclerosis database (TSC1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Feb 01, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asn891fs variant in TSC1 has been reported in 5 individuals with tuberous sclerosis (Jones 1997, Ali 1998, Young 1998) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 891 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TSC1 gene is an established disease mechanism in individuals with tuberous sclerosis. In summary, this variant meets criteria to be classified as pathogenic for tuberous sclerosis in an autosomal dominant manner based upon predicted impact to the protein.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 03, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2672dupA pathogenic mutation, located in coding exon 19 of the TSC1 gene, results from a duplication of A at nucleotide position 2672, causing a translational frameshift with a predicted alternate stop codon (p.N891Kfs*13). This alteration has been identified in multiple individuals diagnosed with tuberous sclerosis and has been reported as 2887insA and 2887-2888insA in the literature (Jones AC et al. Hum. Mol. Genet., 1997 Nov;6:2155-61; Young JM et al. Ann. Hum. Genet., 1998 May;62:203-13; Ali JB et al. J. Med. Genet., 1998 Dec;35:969-72; Dabora SL et al. Ann. Hum. Genet., 1998 Nov;62:491-504). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over