9-132897613-GAAAAAA-GAAAAA

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_000368.5(TSC1):c.2626-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.058 ( 147 hom., cov: 0)

Exomes 𝑓: 0.11 ( 18 hom. )

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12O:1

Conservation

PhyloP100: -0.517

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 -9 ACMG points.

BP6

Variant 9-132897613-GA-G is Benign according to our data. Variant chr9-132897613-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48983.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, not_provided=1, Uncertain_significance=1}. Variant chr9-132897613-GA-G is described in Lovd as [Benign]. Variant chr9-132897613-GA-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.2626-4delT		splice_region_variant, intron_variant	Intron 20 of 22	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.2626-4delT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.2626-4delT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

6083

AN:

104014

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0601

Gnomad AMI

AF:

0.0667

Gnomad AMR

AF:

0.0514

Gnomad ASJ

AF:

0.0821

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.0409

Gnomad MID

AF:

0.0856

Gnomad NFE

AF:

0.0632

Gnomad OTH

AF:

0.0590

GnomAD3 exomes

AF:

0.210

AC:

21819

AN:

103824

Hom.:

AF XY:

0.208

AC XY:

11908

AN XY:

57384

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.165

Gnomad SAS exome

AF:

0.157

Gnomad FIN exome

AF:

0.251

Gnomad NFE exome

AF:

0.224

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.107

AC:

128027

AN:

1199362

Hom.:

Cov.:

AF XY:

0.107

AC XY:

63386

AN XY:

594370

show subpopulations

Gnomad4 AFR exome

AF:

0.168

Gnomad4 AMR exome

AF:

0.129

Gnomad4 ASJ exome

AF:

0.116

Gnomad4 EAS exome

AF:

0.0999

Gnomad4 SAS exome

AF:

0.0811

Gnomad4 FIN exome

AF:

0.122

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.109

GnomAD4 genome

AF:

0.0585

AC:

6080

AN:

104014

Hom.:

147

Cov.:

AF XY:

0.0581

AC XY:

2818

AN XY:

48544

show subpopulations

Gnomad4 AFR

AF:

0.0601

Gnomad4 AMR

AF:

0.0514

Gnomad4 ASJ

AF:

0.0821

Gnomad4 EAS

AF:

0.0102

Gnomad4 SAS

AF:

0.0347

Gnomad4 FIN

AF:

0.0409

Gnomad4 NFE

AF:

0.0633

Gnomad4 OTH

AF:

0.0607

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:4

Aug 17, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Population allele frequency is 19% (rs118203716, 22,767/119,574 alleles in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria is met: BA1. -

Feb 03, 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

- -

Tuberous sclerosis syndrome

Uncertain:1Benign:1Other:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

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

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

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.2626-4delT variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 22671/80186 (1 homozygote, 1/3, frequency: 0.2827302), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC1 variant of 1/40000(0.000025), suggesting this variant is likely a benign polymorphism. Therefore, the variant of interest has been classified as Benign. -

Jun 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 06, 2020

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. -

Dec 09, 2019

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Isolated focal cortical dysplasia type II

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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