9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000368.5(TSC1):​c.2626-4dupT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (26 hom., cov: 0)
  • Exomes 𝑓: 0.12 (1177 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• 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 -16 ACMG points.

• BP6: Variant 9-132897613-G-GA is Benign according to our data. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-G-GA is described in CliVar as Benign/Likely_benign. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00816 (849/104078) while in subpopulation AFR AF = 0.0232 (560/24108). AF 95% confidence interval is 0.0216. There are 26 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 849 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-4dupT		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.2626-4_2626-3insT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-4_2626-3insT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 843 AN: 104078 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00676

Gnomad ASJ AF: 0.00267

Gnomad EAS AF: 0.00941

Gnomad SAS AF: 0.00335

Gnomad FIN AF: 0.00277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.0116

GnomAD2 exomes AF: 0.170 AC: 17641 AN: 103824 AF XY: 0.173

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.116 AC: 140253 AN: 1205502 Hom.: 1177 Cov.: 0 AF XY: 0.117 AC XY: 69804 AN XY: 598492

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

African (AFR) AF: 0.0980 AC: 2672 AN: 27258

American (AMR) AF: 0.131 AC: 3448 AN: 26354

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 2481 AN: 19420

East Asian (EAS) AF: 0.122 AC: 4154 AN: 34050

South Asian (SAS) AF: 0.118 AC: 7473 AN: 63148

European-Finnish (FIN) AF: 0.122 AC: 3905 AN: 32066

Middle Eastern (MID) AF: 0.111 AC: 492 AN: 4416

European-Non Finnish (NFE) AF: 0.116 AC: 109822 AN: 948964

Other (OTH) AF: 0.117 AC: 5806 AN: 49826

⚠️ 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: 0.00816 AC: 849 AN: 104078 Hom.: 26 Cov.: 0 AF XY: 0.00842 AC XY: 409 AN XY: 48572

African (AFR) AF: 0.0232 AC: 560 AN: 24108

American (AMR) AF: 0.00696 AC: 69 AN: 9918

Ashkenazi Jewish (ASJ) AF: 0.00267 AC: 8 AN: 2992

East Asian (EAS) AF: 0.00944 AC: 35 AN: 3708

South Asian (SAS) AF: 0.00336 AC: 10 AN: 2974

European-Finnish (FIN) AF: 0.00277 AC: 10 AN: 3616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.00257 AC: 140 AN: 54454

Other (OTH) AF: 0.0123 AC: 17 AN: 1386

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Nov 25, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Tuberous sclerosis 1 Benign:4

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 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

- -

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. -

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.2626-4dupT variant involves the alteration of a poly-T intronic track. One in silico tool predicts a benign outcome for this variant. 5/5 Alamut algorithms predict no significant change to normal splicing. This variant was found in 13516/80186 control chromosomes (300 homozygotes) at a frequency of 0.1685581, which is approximately 6742 times the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), highly suggesting this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together and based on the high allele frequency in the general population, this variant is classified as Benign. -

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29849115) -

Hereditary cancer-predisposing syndrome Benign:2

Feb 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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. -

Tuberous sclerosis syndrome Benign:1

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Benign:1

May 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: COSV53769953; COSMIC: COSV53769953;