rs118203675

Variant names:

• chr9-132902697-G-A
• rs118203675
• NM_000368.5:c.2299C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132902697-G-A
• chr9-132902697-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000368.5(TSC1):​c.2299C>T​(p.Gln767*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.48
• Publications: 3 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 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

ACMG classification

Our verdict: Pathogenic. The variant received 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 9-132902697-G-A is Pathogenic according to our data. Variant chr9-132902697-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 48936.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2299C>T	p.Gln767*	stop_gained	Exon 18 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.2299C>T	p.Gln767*	stop_gained	Exon 18 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.2299C>T	p.Gln767*	stop_gained	Exon 18 of 23	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2299C>T	p.Gln767*	stop_gained	Exon 18 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2299C>T	p.Gln767*	stop_gained	Exon 19 of 24	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2299C>T	p.Gln767*	stop_gained	Exon 18 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

TSC1-related disorder Pathogenic:1

Dec 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSC1 c.2299C>T variant is predicted to result in premature protein termination (p.Gln767*). This variant was reported in an individual with tuberous sclerosis (Dabora et al. 2001. PubMed ID: 11112665). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in TSC1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		6.5
Vest4		0.95
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs118203675; hg19: chr9-135778084;