9-132896597-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000368.5(TSC1):c.3133C>G(p.Leu1045Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1045F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.17

Publications

0 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060492635).

BP6

Variant 9-132896597-G-C is Benign according to our data. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896597-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 565417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.3133C>G	p.Leu1045Val	missense_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1	Q92574-1Q86WV8X5D9D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 link	c.3133C>G	p.Leu1045Val	missense_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.3133C>G	p.Leu1045Val	missense_variant	Exon 24 of 24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000798

AC:

AN:

250476

AF XY:

0.000103

show subpopulations

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:

0.000163

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000707

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111762

Other (OTH)

AF:

0.0000497

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:3

Aug 15, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 16, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC1: BS1 -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 27, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 11, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TSC1-related disorder

Benign:1

May 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.;T;.;.;T;.;T;.;.;.

Eigen

Benign

-0.077

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

.;D;D;D;D;.;.;.;D;D;.

M_CAP

Benign

0.059

MetaRNN

Benign

0.060

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.3

M;.;M;.;.;M;.;M;.;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.57

N;N;N;.;.;.;.;.;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.13

T;T;T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.29

T;T;T;.;.;.;.;.;.;.;.

Polyphen

0.89

P;.;P;.;.;P;.;P;.;.;.

Vest4

0.17

MutPred

0.16

Gain of glycosylation at S1046 (P = 0.0896);.;Gain of glycosylation at S1046 (P = 0.0896);.;.;Gain of glycosylation at S1046 (P = 0.0896);.;Gain of glycosylation at S1046 (P = 0.0896);.;.;.;

MVP

0.68

MPC

0.52

ClinPred

0.10

GERP RS

4.5

Varity_R

0.076

gMVP

0.19

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over