rs80258442

Positions:

chr9-132928752-T-C

Variant summary

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

The ENST00000298552.9(TSC1):c.106+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,613,860 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 117 hom. )

Consequence

TSC1
ENST00000298552.9 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.926

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 9-132928752-T-C is Benign according to our data. Variant chr9-132928752-T-C is described in ClinVar as [Benign]. Clinvar id is 48737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132928752-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0621 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.106+15A>G		intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 linkuse as main transcript	c.106+15A>G		intron_variant		1	NM_000368.5	ENSP00000298552	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

425

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0684

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00536

AC:

1343

AN:

250390

Hom.:

AF XY:

0.00497

AC XY:

673

AN XY:

135428

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.0701

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00229

AC:

3349

AN:

1461502

Hom.:

117

Cov.:

AF XY:

0.00223

AC XY:

1621

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.0753

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.0000941

Gnomad4 NFE exome

AF:

0.000117

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00277

AC:

422

AN:

152358

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

238

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0680

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000928

Hom.:

Bravo

AF:

0.00303

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	106+15A>G in intron 3 of TSC1: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 9.6% (17/178) of Japanese chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/projects/SN P; dbSNP rs80258442). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2016

Variant summary: The TSC1 c.106+15A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant along with 5/5 in silico splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 630/119968 control chromosomes (26 homozygotes), predominantly observed in the East Asian subpopulation (25 homozygotes) at a frequency of 0.0705565 (601/8518). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in populations of East Asian origin. In addition, one clinical diagnostic laboratory classified this variant as Benign. Taken together, this variant is classified as Benign. -

Isolated focal cortical dysplasia type II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tuberous sclerosis syndrome

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

-0.70

CADD

Benign

5.1

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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