rs7862221

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000368.5(TSC1):c.1335A>G(p.Glu445Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,436 control chromosomes in the GnomAD database, including 17,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. EE445G?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.16 ( 1966 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15107 hom. )

Consequence

TSC1
NM_000368.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0001175

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20O:1

Conservation

PhyloP100: 0.929

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 9-132906834-T-C is Benign according to our data. Variant chr9-132906834-T-C is described in ClinVar as [Benign]. Clinvar id is 48768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906834-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.929 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.1335A>G	p.Glu445Glu	splice_region_variant, synonymous_variant	Exon 14 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.1335A>G	p.Glu445Glu	splice_region_variant, synonymous_variant	Exon 14 of 23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.1335A>G	p.Glu445Glu	splice_region_variant, synonymous_variant	Exon 15 of 24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23723

AN:

152046

Hom.:

1956

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0848

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.148

GnomAD3 exomes

AF:

0.132

AC:

33147

AN:

250852

Hom.:

2331

AF XY:

0.131

AC XY:

17705

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.0881

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.0877

Gnomad SAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.149

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.141

AC:

206428

AN:

1461272

Hom.:

15107

Cov.:

AF XY:

0.140

AC XY:

101534

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.0914

Gnomad4 ASJ exome

AF:

0.149

Gnomad4 EAS exome

AF:

0.0711

Gnomad4 SAS exome

AF:

0.108

Gnomad4 FIN exome

AF:

0.117

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.142

GnomAD4 genome

AF:

0.156

AC:

23760

AN:

152164

Hom.:

1966

Cov.:

AF XY:

0.151

AC XY:

11201

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.213

Gnomad4 AMR

AF:

0.104

Gnomad4 ASJ

AF:

0.148

Gnomad4 EAS

AF:

0.0850

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.150

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.150

Hom.:

3049

Bravo

AF:

0.158

Asia WGS

AF:

0.128

AC:

449

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.150

ClinVar

Significance: Benign

Submissions summary: Benign:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2013

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu445Glu in exon 14 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 21.9% (965/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs7862221). -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Tuberous sclerosis 1

Benign:7

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2020

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

May 26, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The TSC1 c.1335A>G (p.Glu445Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change 2 nucleotides from the exon14-intron13 boundary. One in silico tool predicts a polymorphism outcome for this variant. 5/5 Alamut algorithms predict no significant change to the cononical splice acceptor site, while 2/5 predict a strengthening of a cryptic splice acceptor site. This variant was found in 16480/120190 control chromosomes (1225 homozygotes) at a frequency of 0.1371162, which is approximately 5485 times the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign, and it has been reported in the literature as a normal population variant (PMID: 18538015). Taken together and based on the high allele frequency in the general population, this variant is classified as Benign. -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tuberous sclerosis syndrome

Benign:1Other:1

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: 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

- -

Isolated focal cortical dysplasia type II

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Nov 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.038

SpliceAI score (max)

0.14

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