9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_000368.5(TSC1):c.2626-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.058 ( 147 hom., cov: 0)

Exomes 𝑓: 0.11 ( 18 hom. )

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14O:1

Conservation

PhyloP100: -0.517

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, 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

new If you want to explore the variant's impact on the transcript NM_000368.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 9-132897613-GA-G is Benign according to our data. Variant chr9-132897613-GA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48983.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0615 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	UniProt
TSC1	NM_000368.5	MANE Select	c.2626-4delT	splice_region intron	N/A	NP_000359.1	Q92574-1
TSC1	NM_001406592.1		c.2626-4delT	splice_region intron	N/A	NP_001393521.1	X5D9D2
TSC1	NM_001406593.1		c.2626-4delT	splice_region intron	N/A	NP_001393522.1	Q92574-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-4delT	splice_region intron	N/A	ENSP00000298552.3	Q92574-1
TSC1	ENST00000490179.4	TSL:3	c.2626-4delT	splice_region intron	N/A	ENSP00000495533.2	Q92574-1
TSC1	ENST00000643875.1		c.2626-4delT	splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

6083

AN:

104014

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0601

Gnomad AMI

AF:

0.0667

Gnomad AMR

AF:

0.0514

Gnomad ASJ

AF:

0.0821

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.0409

Gnomad MID

AF:

0.0856

Gnomad NFE

AF:

0.0632

Gnomad OTH

AF:

0.0590

GnomAD2 exomes

AF:

0.210

AC:

21819

AN:

103824

AF XY:

0.208

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.251

Gnomad NFE exome

AF:

0.224

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.107

AC:

128027

AN:

1199362

Hom.:

Cov.:

AF XY:

0.107

AC XY:

63386

AN XY:

594370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.168

AC:

4397

AN:

26202

American (AMR)

AF:

0.129

AC:

3177

AN:

24578

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

2247

AN:

19366

East Asian (EAS)

AF:

0.0999

AC:

3308

AN:

33102

South Asian (SAS)

AF:

0.0811

AC:

5017

AN:

61854

European-Finnish (FIN)

AF:

0.122

AC:

3809

AN:

31344

Middle Eastern (MID)

AF:

0.161

AC:

706

AN:

4386

European-Non Finnish (NFE)

AF:

0.105

AC:

99942

AN:

948990

Other (OTH)

AF:

0.109

AC:

5424

AN:

49540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.328

Heterozygous variant carriers

7262

14524

21787

29049

36311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3754

7508

11262

15016

18770

<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:

0.0585

AC:

6080

AN:

104014

Hom.:

147

Cov.:

AF XY:

0.0581

AC XY:

2818

AN XY:

48544

show subpopulations

African (AFR)

AF:

0.0601

AC:

1449

AN:

24112

American (AMR)

AF:

0.0514

AC:

509

AN:

9912

Ashkenazi Jewish (ASJ)

AF:

0.0821

AC:

245

AN:

2984

East Asian (EAS)

AF:

0.0102

AC:

AN:

3710

South Asian (SAS)

AF:

0.0347

AC:

103

AN:

2970

European-Finnish (FIN)

AF:

0.0409

AC:

148

AN:

3620

Middle Eastern (MID)

AF:

0.0750

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.0633

AC:

3441

AN:

54402

Other (OTH)

AF:

0.0607

AC:

AN:

1384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

212

425

637

850

1062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Tuberous sclerosis 1 (4)

Tuberous sclerosis syndrome (4)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.52

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over