9-132901734-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000368.5(TSC1):c.2392-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,602,802 control chromosomes in the GnomAD database, including 20,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3489 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16515 hom. )

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.131

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 9-132901734-A-G is Benign according to our data. Variant chr9-132901734-A-G is described in ClinVar as Benign. ClinVar VariationId is 48948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.2392-35T>C		intron_variant	Intron 18 of 22	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.2392-35T>C		intron_variant	Intron 18 of 22	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.2392-35T>C		intron_variant	Intron 19 of 23	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29414

AN:

151994

Hom.:

3474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.342

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0848

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.172

GnomAD2 exomes

AF:

0.142

AC:

35526

AN:

249528

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.349

Gnomad AMR exome

AF:

0.0945

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.0875

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.145

AC:

210897

AN:

1450690

Hom.:

16515

Cov.:

AF XY:

0.143

AC XY:

103494

AN XY:

722396

show subpopulations

African (AFR)

AF:

0.349

AC:

11630

AN:

33284

American (AMR)

AF:

0.0984

AC:

4398

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3894

AN:

26092

East Asian (EAS)

AF:

0.0711

AC:

2819

AN:

39638

South Asian (SAS)

AF:

0.108

AC:

9323

AN:

86066

European-Finnish (FIN)

AF:

0.118

AC:

6084

AN:

51584

Middle Eastern (MID)

AF:

0.115

AC:

661

AN:

5752

European-Non Finnish (NFE)

AF:

0.148

AC:

163063

AN:

1103494

Other (OTH)

AF:

0.150

AC:

9025

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

9238

18477

27715

36954

46192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5778

11556

17334

23112

28890

<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:

0.194

AC:

29462

AN:

152112

Hom.:

3489

Cov.:

AF XY:

0.187

AC XY:

13907

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.343

AC:

14195

AN:

41444

American (AMR)

AF:

0.116

AC:

1770

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

513

AN:

3468

East Asian (EAS)

AF:

0.0850

AC:

440

AN:

5174

South Asian (SAS)

AF:

0.107

AC:

518

AN:

4828

European-Finnish (FIN)

AF:

0.117

AC:

1241

AN:

10598

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.151

AC:

10281

AN:

67986

Other (OTH)

AF:

0.176

AC:

373

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1156

2311

3467

4622

5778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.178

Hom.:

1469

Bravo

AF:

0.200

Asia WGS

AF:

0.135

AC:

473

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with tuberous sclerosis -

Dec 22, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 10533066, 17304050) -

Tuberous sclerosis 1

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis syndrome

Other:1

Tuberous sclerosis database (TSC1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.8

(source)

DANN

Benign

0.28

PhyloP100

0.13

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over