NM_000368.5:c.1142-33A>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.1142-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,106 control chromosomes in the GnomAD database, including 15,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.15 ( 1834 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13383 hom. )

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 0.194

Publications

13 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 9-132910725-T-C is Benign according to our data. Variant chr9-132910725-T-C is described in ClinVar as Benign. ClinVar VariationId is 48747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.1142-33A>G		intron_variant	Intron 11 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.1142-33A>G		intron_variant	Intron 11 of 22	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.1142-33A>G		intron_variant	Intron 12 of 23	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22847

AN:

152062

Hom.:

1824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.0848

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.143

GnomAD2 exomes

AF:

0.125

AC:

30855

AN:

246716

AF XY:

0.123

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0858

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.0875

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.133

AC:

193632

AN:

1459926

Hom.:

13383

Cov.:

AF XY:

0.131

AC XY:

95332

AN XY:

726216

show subpopulations

African (AFR)

AF:

0.217

AC:

7252

AN:

33436

American (AMR)

AF:

0.0890

AC:

3979

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

3682

AN:

26136

East Asian (EAS)

AF:

0.0710

AC:

2820

AN:

39700

South Asian (SAS)

AF:

0.105

AC:

9037

AN:

86204

European-Finnish (FIN)

AF:

0.104

AC:

5464

AN:

52760

Middle Eastern (MID)

AF:

0.107

AC:

524

AN:

4876

European-Non Finnish (NFE)

AF:

0.137

AC:

152800

AN:

1111808

Other (OTH)

AF:

0.134

AC:

8074

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

9413

18826

28240

37653

47066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5420

10840

16260

21680

27100

<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:

0.150

AC:

22885

AN:

152180

Hom.:

1834

Cov.:

AF XY:

0.145

AC XY:

10782

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.212

AC:

8816

AN:

41498

American (AMR)

AF:

0.103

AC:

1576

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

482

AN:

3470

East Asian (EAS)

AF:

0.0850

AC:

441

AN:

5186

South Asian (SAS)

AF:

0.104

AC:

503

AN:

4822

European-Finnish (FIN)

AF:

0.103

AC:

1093

AN:

10604

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9538

AN:

67998

Other (OTH)

AF:

0.148

AC:

312

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

968

1936

2903

3871

4839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.139

Hom.:

2346

Bravo

AF:

0.153

Asia WGS

AF:

0.127

AC:

444

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis 1

Benign:1

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

- -

Malignant tumor of urinary bladder

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

0.78

(source)

DANN

Benign

0.72

PhyloP100

0.19

BranchPoint Hunter

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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