rs10901220

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.1439-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,596,800 control chromosomes in the GnomAD database, including 16,930 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 0.16 ( 1982 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14948 hom. )

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.466

Publications

14 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 rather VUS (scored 5 / 10). 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=-0.86).

BP6

Variant 9-132906176-G-A is Benign according to our data. Variant chr9-132906176-G-A is described in ClinVar as Benign. ClinVar VariationId is 48784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSC1	NM_000368.5	MANE Select	c.1439-37C>T	intron	N/A	NP_000359.1
TSC1	NM_001406592.1		c.1439-37C>T	intron	N/A	NP_001393521.1
TSC1	NM_001406593.1		c.1439-37C>T	intron	N/A	NP_001393522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1439-37C>T	intron	N/A	ENSP00000298552.3
TSC1	ENST00000490179.4	TSL:3	c.1439-37C>T	intron	N/A	ENSP00000495533.2
TSC1	ENST00000644882.1		n.357C>T	non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23788

AN:

152046

Hom.:

1972

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0845

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.148

GnomAD2 exomes

AF:

0.134

AC:

28969

AN:

216852

AF XY:

0.132

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.0897

Gnomad ASJ exome

AF:

0.152

Gnomad EAS exome

AF:

0.0897

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.137

GnomAD4 exome

AF:

0.142

AC:

204534

AN:

1444636

Hom.:

14948

Cov.:

AF XY:

0.140

AC XY:

100430

AN XY:

717480

show subpopulations

African (AFR)

AF:

0.219

AC:

7272

AN:

33274

American (AMR)

AF:

0.0918

AC:

3919

AN:

42702

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3852

AN:

25842

East Asian (EAS)

AF:

0.0715

AC:

2820

AN:

39458

South Asian (SAS)

AF:

0.108

AC:

9050

AN:

84082

European-Finnish (FIN)

AF:

0.117

AC:

6027

AN:

51310

Middle Eastern (MID)

AF:

0.117

AC:

525

AN:

4506

European-Non Finnish (NFE)

AF:

0.147

AC:

162602

AN:

1103670

Other (OTH)

AF:

0.142

AC:

8467

AN:

59792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

9351

18702

28053

37404

46755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5748

11496

17244

22992

28740

<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:

0.157

AC:

23828

AN:

152164

Hom.:

1982

Cov.:

AF XY:

0.151

AC XY:

11229

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.214

AC:

8896

AN:

41520

American (AMR)

AF:

0.104

AC:

1592

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

513

AN:

3470

East Asian (EAS)

AF:

0.0847

AC:

438

AN:

5172

South Asian (SAS)

AF:

0.106

AC:

509

AN:

4820

European-Finnish (FIN)

AF:

0.116

AC:

1235

AN:

10602

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.150

AC:

10195

AN:

67974

Other (OTH)

AF:

0.153

AC:

323

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1033

2065

3098

4130

5163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.153

Hom.:

1410

Bravo

AF:

0.159

Asia WGS

AF:

0.130

AC:

453

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

6.9

(source)

DANN

Benign

0.44

PhyloP100

0.47

BranchPoint Hunter

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over