Genetic Variant TSC1:c.364-1038C>A (chr9-132924530-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000368.5(TSC1):c.364-1038C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 151,946 control chromosomes in the GnomAD database, including 36,577 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 36577 hom., cov: 31)

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.910

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, 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.364-1038C>A		intron_variant	Intron 5 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.364-1038C>A		intron_variant	Intron 5 of 22	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.364-1038C>A		intron_variant	Intron 6 of 23	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.693

AC:

105249

AN:

151828

Hom.:

36539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.642

Gnomad AMI

AF:

0.635

Gnomad AMR

AF:

0.683

Gnomad ASJ

AF:

0.780

Gnomad EAS

AF:

0.666

Gnomad SAS

AF:

0.758

Gnomad FIN

AF:

0.706

Gnomad MID

AF:

0.640

Gnomad NFE

AF:

0.719

Gnomad OTH

AF:

0.679

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.693

AC:

105345

AN:

151946

Hom.:

36577

Cov.:

AF XY:

0.695

AC XY:

51562

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.642

AC:

26583

AN:

41398

American (AMR)

AF:

0.684

AC:

10433

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.780

AC:

2705

AN:

3466

East Asian (EAS)

AF:

0.665

AC:

3441

AN:

5174

South Asian (SAS)

AF:

0.759

AC:

3652

AN:

4814

European-Finnish (FIN)

AF:

0.706

AC:

7453

AN:

10558

Middle Eastern (MID)

AF:

0.627

AC:

183

AN:

292

European-Non Finnish (NFE)

AF:

0.719

AC:

48874

AN:

67964

Other (OTH)

AF:

0.683

AC:

1442

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1690

3379

5069

6758

8448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.638

Hom.:

2221

Bravo

AF:

0.684

Asia WGS

AF:

0.718

AC:

2481

AN:

3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

4.9

(source)

DANN

Benign

0.43

PhyloP100

0.91

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over