9-132897613-GAAAAAAAAAAAA-GAAAAAAA

Variant names:

• chr9-132897613-GAAAAA-G
• rs5901000
• NM_000368.5:c.2626-8_2626-4delTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000368.5(TSC1):​c.2626-8_2626-4delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000718 in 1,253,568 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18
• 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 -8 ACMG points.

• BP6: Variant 9-132897613-GAAAAA-G is Benign according to our data. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAAAAA-G is described in CliVar as Likely_benign. Clinvar id is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-8_2626-4delTTTTT		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.2626-8_2626-4delTTTTT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-8_2626-4delTTTTT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000718 AC: 90 AN: 1253568 Hom.: 0 AF XY: 0.0000658 AC XY: 41 AN XY: 623066

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

African (AFR) AF: 0.000177 AC: 5 AN: 28198

American (AMR) AF: 0.0000734 AC: 2 AN: 27244

Ashkenazi Jewish (ASJ) AF: 0.0000495 AC: 1 AN: 20200

East Asian (EAS) AF: 0.0000846 AC: 3 AN: 35446

South Asian (SAS) AF: 0.0000305 AC: 2 AN: 65636

European-Finnish (FIN) AF: 0.000121 AC: 4 AN: 33122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4556

European-Non Finnish (NFE) AF: 0.0000699 AC: 69 AN: 987422

Other (OTH) AF: 0.0000773 AC: 4 AN: 51744

⚠️ 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 Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 02, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TSC1-related disorder Benign:1

Jun 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Jul 26, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=76/24	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;