rs118203657

Variant summary

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

The NM_000368.5(TSC1):​c.2194C>T​(p.His732Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,612,416 control chromosomes in the GnomAD database, including 28 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 0.0033 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0036 ( 24 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

1
11
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:27O:2

Conservation

PhyloP100: 8.07
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]

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=0.00885722).
BP6
Variant 9-132903665-G-A is Benign according to our data. Variant chr9-132903665-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5103.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=18, Likely_benign=3, not_provided=2}. Variant chr9-132903665-G-A is described in Lovd as [Likely_benign]. Variant chr9-132903665-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00326 (497/152322) while in subpopulation NFE AF= 0.00463 (315/68032). AF 95% confidence interval is 0.00421. There are 4 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 497 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.2194C>T p.His732Tyr missense_variant Exon 17 of 23 ENST00000298552.9 NP_000359.1 Q92574-1Q86WV8X5D9D2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC1ENST00000298552.9 linkc.2194C>T p.His732Tyr missense_variant Exon 17 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.2194C>T p.His732Tyr missense_variant Exon 18 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
AF:
0.00327
AC:
497
AN:
152204
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0138
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00463
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00364
AC:
914
AN:
251112
Hom.:
5
AF XY:
0.00357
AC XY:
484
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.000984
Gnomad AMR exome
AF:
0.00121
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0138
Gnomad NFE exome
AF:
0.00474
Gnomad OTH exome
AF:
0.00327
GnomAD4 exome
AF:
0.00364
AC:
5309
AN:
1460094
Hom.:
24
Cov.:
32
AF XY:
0.00348
AC XY:
2527
AN XY:
726338
show subpopulations
Gnomad4 AFR exome
AF:
0.000449
Gnomad4 AMR exome
AF:
0.00125
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0140
Gnomad4 NFE exome
AF:
0.00387
Gnomad4 OTH exome
AF:
0.00302
GnomAD4 genome
AF:
0.00326
AC:
497
AN:
152322
Hom.:
4
Cov.:
32
AF XY:
0.00357
AC XY:
266
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000601
Gnomad4 AMR
AF:
0.000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0138
Gnomad4 NFE
AF:
0.00463
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00361
Hom.:
1
Bravo
AF:
0.00213
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00389
AC:
15
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00360
AC:
31
ExAC
AF:
0.00386
AC:
469
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00333
EpiControl
AF:
0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:27Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:9Other:1
Jan 02, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 17, 2014
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 25, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.5% (96/6614) Finnish chromosomes -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 24, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 09, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:8
Dec 01, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Oct 14, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TSC1: PP2, BS2 -

Jun 22, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 03, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tuberous sclerosis 1 Benign:7
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 17, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 21, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
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

- -

Jul 06, 2023
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

Sep 20, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Isolated focal cortical dysplasia type II Uncertain:1Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 01, 2017
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

this variant was indentified in an individual with malformations of cortical development -

Hereditary cancer-predisposing syndrome Benign:2
Oct 21, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 20, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Focal cortical dysplasia of Taylor type 2B Uncertain:1
Jun 01, 2009
OMIM
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: literature only

- -

Tuberous sclerosis syndrome Other:1
-
Tuberous sclerosis database (TSC1)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D;.;D;.;.;D;.;D;.;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.81
.;T;T;T;T;.;.;.;T;T;.
MetaRNN
Benign
0.0089
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.014
T
MutationAssessor
Benign
1.6
L;.;L;.;.;L;.;L;.;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-2.9
D;D;D;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.34
Sift
Uncertain
0.0080
D;D;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.037
D;D;D;.;.;.;.;.;.;.;.
Polyphen
0.99
D;.;D;.;.;D;.;D;.;.;.
Vest4
0.44
MVP
0.56
MPC
0.58
ClinPred
0.045
T
GERP RS
5.3
Varity_R
0.29
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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.

Other links and lift over

dbSNP: rs118203657; hg19: chr9-135779052; COSMIC: COSV104404438; COSMIC: COSV104404438; API