chr9-132910483-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000493467.6(TSC1):n.622A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,606,576 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 12 hom. )

Consequence

TSC1
ENST00000493467.6 non_coding_transcript_exon

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:3

Conservation

PhyloP100: -1.25

Publications

2 publications found

Variant links:

COSMIC-nc: COSV104404440

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 (MetaRNN=0.005337715).

BP6

Variant 9-132910483-T-C is Benign according to our data. Variant chr9-132910483-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152356) while in subpopulation NFE AF = 0.00438 (298/68046). AF 95% confidence interval is 0.00397. There are 1 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.1263+88A>G		intron_variant	Intron 12 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 link	c.1263+88A>G		intron_variant	Intron 12 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4 link	c.1263+88A>G		intron_variant	Intron 13 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

366

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00438

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00236

AC:

588

AN:

248920

AF XY:

0.00242

show subpopulations

Gnomad AFR exome

AF:

0.000688

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00149

Gnomad NFE exome

AF:

0.00427

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00369

AC:

5368

AN:

1454220

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

2580

AN XY:

723746

show subpopulations

African (AFR)

AF:

0.000570

AC:

AN:

33334

American (AMR)

AF:

0.000581

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.000999

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00145

AC:

AN:

52580

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00450

AC:

4975

AN:

1105830

Other (OTH)

AF:

0.00291

AC:

175

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

303

606

910

1213

1516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.00240

AC:

366

AN:

152356

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41568

American (AMR)

AF:

0.000392

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00438

AC:

298

AN:

68046

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00277

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00363

AC:

ExAC

AF:

0.00233

AC:

283

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC1: BS2 -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Tuberous sclerosis syndrome

Other:2

Tuberous sclerosis database (TSC1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Tuberous sclerosis database (TSC1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.23

(source)

DANN

Benign

0.58

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.31

.;.;T;T

MetaRNN

Benign

0.0053

T;T;T;T

PhyloP100

-1.3

Polyphen

0.0

B;B;B;.

GERP RS

-2.8

Mutation Taster

=100/0

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