rs118203400

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_001406626.1(TSC1):​c.-310C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000589 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

TSC1
NM_001406626.1 5_prime_UTR_premature_start_codon_gain

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10O:1

Conservation

PhyloP100: 6.52
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.878
BP6
Variant 9-132921914-G-A is Benign according to our data. Variant chr9-132921914-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49057.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=1, not_provided=1}. Variant chr9-132921914-G-A is described in Lovd as [Likely_benign]. Variant chr9-132921914-G-A is described in Lovd as [Benign].
BS2
High AC in GnomAdExome4 at 91 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.568C>T p.Arg190Cys missense_variant Exon 7 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.568C>T p.Arg190Cys missense_variant Exon 7 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.568C>T p.Arg190Cys missense_variant Exon 8 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251360
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135846
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000622
AC:
91
AN:
1461876
Hom.:
0
Cov.:
32
AF XY:
0.0000481
AC XY:
35
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000936
Gnomad4 NFE exome
AF:
0.0000701
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000494
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:10Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 28, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19747374, 21309039, 10227394, 23857276, 26517685) -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Tuberous sclerosis 1 Benign:3
Dec 18, 2017
Genomic Research Center, Shahid Beheshti University of Medical Sciences
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

- -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
May 04, 2019
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. -

Feb 11, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Tuberous sclerosis syndrome Benign:1Other:1
Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

TSC1-related disorder Uncertain:1
Feb 14, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The TSC1 c.568C>T variant is predicted to result in the amino acid substitution p.Arg190Cys. This variant has been reported in individuals affected with tuberous sclerosis complex (Mozaffari et al. 2009. PubMed ID: 19747374; Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039). Functional studies showed the signals in cells expressing the TSC1 variant was not significantly different from the signal in cells expressing wild-type TSC1 and this variant was considered a neutral variant (Mozaffari et al. 2009. PubMed ID: 19747374). It was also identified in an individual with Lynch syndrome (Table S3, Jóri et al. 2015. PubMed ID: 26517685). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity ranging from benign to uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/49057/). An alternative variant at the same amino acid (p.Arg190Pro) has been reported causative in patients with tuberous sclerosis complex (Mozaffari et al. 2009. PubMed ID: 19747374; Table S1, Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Uncertain
2.5
M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.7
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;T;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen
0.98
D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.
Vest4
0.96
MVP
0.97
MPC
1.5
ClinPred
0.58
D
GERP RS
6.1
Varity_R
0.68
gMVP
0.81

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.

Other links and lift over

dbSNP: rs118203400; hg19: chr9-135797301; COSMIC: COSV53769094; COSMIC: COSV53769094; API