chr9-132906118-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000368.5(TSC1):c.1460C>G(p.Ser487Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000227 in 1,613,372 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14O:1

Conservation

PhyloP100: 4.84

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02551487).

BP6

Variant 9-132906118-G-C is Benign according to our data. Variant chr9-132906118-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41690.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=5, Uncertain_significance=1, not_provided=1}. Variant chr9-132906118-G-C is described in Lovd as [Benign]. Variant chr9-132906118-G-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000263 (40/152354) while in subpopulation EAS AF= 0.00289 (15/5184). AF 95% confidence interval is 0.00178. There are 1 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.1460C>G	p.Ser487Cys	missense_variant	Exon 15 of 23	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.1460C>G	p.Ser487Cys	missense_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.1460C>G	p.Ser487Cys	missense_variant	Exon 16 of 24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000448

AC:

110

AN:

245778

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

133548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00301

Gnomad EAS exome

AF:

0.00180

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000223

AC:

326

AN:

1461018

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

193

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00329

Gnomad4 EAS exome

AF:

0.00149

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000263

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000335

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:14Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:5

Oct 29, 2019

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is present in approximately 1/280 individuals in an unaffected control population of East Asian ancestry (gnomAD). This variant has been reported in one individual with Tuberous Sclerosis (TSC1) (Choi et al., 2006). However, it was considered to be likely neutral by functional studies (Hoogeveen_Westerveld et al., 2011). Furthermore, this variant was identified as an incidental finding in one individual in a series of 566 individuals undergoing exome sequencing (Johnston et al., 2012). This variant is listed in ClinVar (Variation ID: 41690). Family studies were performed and showed that this variant was inherited from an unaffected parent who has no features of TSC1-related disorders. Additionally, the patient's clinical features do not match a TSC phenotype. -

Jul 03, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC1: BS1 -

Apr 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21309039, 27153395, 16554133, 23514105, 22703879, 31054281) -

Jun 09, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Dec 06, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Oct 27, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 08, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Tuberous sclerosis syndrome

Benign:1Other:1

Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Aug 31, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primitive neuroectodermal tumor

Uncertain:1

Mar 21, 2016

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated focal cortical dysplasia type II

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

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

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

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

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.026

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

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.4

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.48

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

REVEL

Uncertain

0.43

Sift

Benign

0.045

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

Sift4G

Benign

0.091

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

Polyphen

1.0

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

Vest4

0.61

MVP

0.63

MPC

1.4

ClinPred

0.057

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.11

gMVP

0.44

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