rs118203504

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000368.5(TSC1):c.1208C>T(p.Ser403Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000412 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16O:2

Conservation

PhyloP100: 5.61

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 -17 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.11989471).

BP6

Variant 9-132910626-G-A is Benign according to our data. Variant chr9-132910626-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132910626-G-A is described in Lovd as [Likely_benign]. Variant chr9-132910626-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000328 (50/152278) while in subpopulation NFE AF= 0.000632 (43/68022). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.1208C>T	p.Ser403Leu	missense_variant	12/23	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.1208C>T	p.Ser403Leu	missense_variant	12/23	1	NM_000368.5	ENSP00000298552	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251090

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000421

AC:

615

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

286

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000494

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000328

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000582

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	This variant is associated with the following publications: (PMID: 23514105, 28873162, 27930734, 24728327, 31623367) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TSC1: BS1 -

not specified

Benign:4Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2021	Variant summary: TSC1 c.1208C>T (p.Ser403Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251090 control chromosomes, predominantly at a frequency of 0.00061 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1208C>T in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Tuberous sclerosis 1

Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 05, 2021	- -

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

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;D;.;D;.;D;.;.;.;.;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

.;D;D;D;.;.;.;D;D;.;.;.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.3

M;.;M;.;M;.;M;.;.;.;.;.;.;.

MutationTaster

Benign

0.90

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.2

N;N;N;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.28

T;T;T;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.17

T;T;T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.77

P;.;P;.;P;.;P;.;.;.;P;P;P;.

Vest4

0.51

MVP

0.54

MPC

0.47

ClinPred

0.028

GERP RS

4.9

Varity_R

0.035

gMVP

0.36

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

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