rs6597586

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000368.5(TSC1):c.1142-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,106 control chromosomes in the GnomAD database, including 15,217 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 0.15 ( 1834 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13383 hom. )

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 0.194

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 links:

TSC1 (HGNC:):

TSC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 9-132910725-T-C is Benign according to our data. Variant chr9-132910725-T-C is described in ClinVar as [Benign]. Clinvar id is 48747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132910725-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.1142-33A>G		intron_variant		ENST00000298552.9	NP_000359.1	Q92574-1Q86WV8X5D9D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 linkuse as main transcript	c.1142-33A>G		intron_variant		1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 linkuse as main transcript	c.1142-33A>G		intron_variant		3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22847

AN:

152062

Hom.:

1824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.0848

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.143

GnomAD3 exomes

AF:

0.125

AC:

30855

AN:

246716

Hom.:

2064

AF XY:

0.123

AC XY:

16433

AN XY:

133464

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0858

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.0875

Gnomad SAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.133

AC:

193632

AN:

1459926

Hom.:

13383

Cov.:

AF XY:

0.131

AC XY:

95332

AN XY:

726216

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.0890

Gnomad4 ASJ exome

AF:

0.141

Gnomad4 EAS exome

AF:

0.0710

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.104

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.134

GnomAD4 genome

AF:

0.150

AC:

22885

AN:

152180

Hom.:

1834

Cov.:

AF XY:

0.145

AC XY:

10782

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.139

Gnomad4 EAS

AF:

0.0850

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.103

Gnomad4 NFE

AF:

0.140

Gnomad4 OTH

AF:

0.148

Alfa

AF:

0.134

Hom.:

1489

Bravo

AF:

0.153

Asia WGS

AF:

0.127

AC:

444

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Tuberous sclerosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Tuberous sclerosis syndrome

Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

- -

Malignant tumor of urinary bladder

Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.78

DANN

Benign

0.72

BranchPoint Hunter

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over