Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000368.5(TSC1):c.1335A>G(p.Glu445Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,436 control chromosomes in the GnomAD database, including 17,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1966 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15107 hom. )

Consequence

TSC1
NM_000368.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0001175

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: 0.929

Publications

37 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 9-132906834-T-C is Benign according to our data. Variant chr9-132906834-T-C is described in ClinVar as Benign. ClinVar VariationId is 48768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.929 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 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	HGVSp	Effect	Exon Rank	Protein
TSC1	NM_000368.5	MANE Select	c.1335A>G	p.Glu445Glu	splice_region synonymous	Exon 14 of 23	NP_000359.1
TSC1	NM_001406592.1		c.1335A>G	p.Glu445Glu	splice_region synonymous	Exon 14 of 23	NP_001393521.1
TSC1	NM_001406593.1		c.1335A>G	p.Glu445Glu	splice_region synonymous	Exon 14 of 23	NP_001393522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1335A>G	p.Glu445Glu	splice_region synonymous	Exon 14 of 23	ENSP00000298552.3
TSC1	ENST00000490179.4	TSL:3	c.1335A>G	p.Glu445Glu	splice_region synonymous	Exon 15 of 24	ENSP00000495533.2
TSC1	ENST00000643875.1		c.1335A>G	p.Glu445Glu	splice_region synonymous	Exon 14 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23723

AN:

152046

Hom.:

1956

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0848

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:

0.132

AC:

33147

AN:

250852

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.0881

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.0877

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.149

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.141

AC:

206428

AN:

1461272

Hom.:

15107

Cov.:

AF XY:

0.140

AC XY:

101534

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.217

AC:

7260

AN:

33464

American (AMR)

AF:

0.0914

AC:

4086

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3895

AN:

26126

East Asian (EAS)

AF:

0.0711

AC:

2823

AN:

39688

South Asian (SAS)

AF:

0.108

AC:

9318

AN:

86242

European-Finnish (FIN)

AF:

0.117

AC:

6240

AN:

53300

Middle Eastern (MID)

AF:

0.109

AC:

627

AN:

5766

European-Non Finnish (NFE)

AF:

0.147

AC:

163624

AN:

1111584

Other (OTH)

AF:

0.142

AC:

8555

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

9041

18082

27122

36163

45204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5766

11532

17298

23064

28830

<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:

0.156

AC:

23760

AN:

152164

Hom.:

1966

Cov.:

AF XY:

0.151

AC XY:

11201

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.213

AC:

8830

AN:

41484

American (AMR)

AF:

0.104

AC:

1591

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

513

AN:

3470

East Asian (EAS)

AF:

0.0850

AC:

440

AN:

5178

South Asian (SAS)

AF:

0.105

AC:

508

AN:

4818

European-Finnish (FIN)

AF:

0.116

AC:

1230

AN:

10600

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.150

AC:

10200

AN:

68008

Other (OTH)

AF:

0.152

AC:

321

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1007

2014

3022

4029

5036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.152

Hom.:

6593

Bravo

AF:

0.158

Asia WGS

AF:

0.128

AC:

449

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.150

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Tuberous sclerosis 1 (7)

not provided (3)

Tuberous sclerosis syndrome (3)

Hereditary cancer-predisposing syndrome (1)

Isolated focal cortical dysplasia type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=64/36

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.038

SpliceAI score (max)

0.14

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.

rs7862221

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