9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAA

Variant names:

• chr9-132897613-GA-G
• rs5901000
• NM_000368.5:c.2626-4delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14 O:1
• Conservation: PhyloP100: -0.517
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 9-132897613-GA-G is Benign according to our data. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983. Variant chr9-132897613-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 48983.
• 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	c.2626-4delT		splice_region_variant, intron_variant	Intron 20 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-4delT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-4delT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 6083 AN: 104014 Hom.: 147 Cov.: 0

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

GnomAD2 exomes AF: 0.210 AC: 21819 AN: 103824 AF XY: 0.208

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 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.: 18 Cov.: 0 AF XY: 0.107 AC XY: 63386 AN XY: 594370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.168 AC: 4397 AN: 26202

American (AMR) AF: 0.129 AC: 3177 AN: 24578

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 2247 AN: 19366

East Asian (EAS) AF: 0.0999 AC: 3308 AN: 33102

South Asian (SAS) AF: 0.0811 AC: 5017 AN: 61854

European-Finnish (FIN) AF: 0.122 AC: 3809 AN: 31344

Middle Eastern (MID) AF: 0.161 AC: 706 AN: 4386

European-Non Finnish (NFE) AF: 0.105 AC: 99942 AN: 948990

Other (OTH) AF: 0.109 AC: 5424 AN: 49540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0585 AC: 6080 AN: 104014 Hom.: 147 Cov.: 0 AF XY: 0.0581 AC XY: 2818 AN XY: 48544

African (AFR) AF: 0.0601 AC: 1449 AN: 24112

American (AMR) AF: 0.0514 AC: 509 AN: 9912

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 245 AN: 2984

East Asian (EAS) AF: 0.0102 AC: 38 AN: 3710

South Asian (SAS) AF: 0.0347 AC: 103 AN: 2970

European-Finnish (FIN) AF: 0.0409 AC: 148 AN: 3620

Middle Eastern (MID) AF: 0.0750 AC: 15 AN: 200

European-Non Finnish (NFE) AF: 0.0633 AC: 3441 AN: 54402

Other (OTH) AF: 0.0607 AC: 84 AN: 1384

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1 Benign:3 Other:1

Feb 04, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Aug 17, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 1 Benign:4

Apr 28, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

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

Jun 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000; COSMIC: COSV53765160; COSMIC: COSV53765160;