9-132897613-GAAAAAAAAAAAA-GAAAAAAAAA

Variant names:

• chr9-132897613-GAAA-G
• rs5901000
• NM_000368.5:c.2626-6_2626-4delTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000368.5(TSC1):​c.2626-6_2626-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,350,302 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. 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 0.000029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.485
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 9-132897613-GAAA-G is Benign according to our data. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092. Variant chr9-132897613-GAAA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 466092.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-6_2626-4delTTT		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.2626-6_2626-4delTTT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-6_2626-4delTTT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.0000288 AC: 3 AN: 104134 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000806

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00162 AC: 2014 AN: 1246168 Hom.: 0 AF XY: 0.00163 AC XY: 1009 AN XY: 619228

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

African (AFR) AF: 0.00233 AC: 65 AN: 27842

American (AMR) AF: 0.00351 AC: 95 AN: 27060

Ashkenazi Jewish (ASJ) AF: 0.00294 AC: 59 AN: 20044

East Asian (EAS) AF: 0.00228 AC: 80 AN: 35098

South Asian (SAS) AF: 0.00109 AC: 71 AN: 65354

European-Finnish (FIN) AF: 0.00357 AC: 117 AN: 32814

Middle Eastern (MID) AF: 0.000883 AC: 4 AN: 4532

European-Non Finnish (NFE) AF: 0.00142 AC: 1393 AN: 982010

Other (OTH) AF: 0.00253 AC: 130 AN: 51414

⚠️ 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: 0.0000288 AC: 3 AN: 104134 Hom.: 0 Cov.: 0 AF XY: 0.0000412 AC XY: 2 AN XY: 48598

African (AFR) AF: 0.00 AC: 0 AN: 24134

American (AMR) AF: 0.00 AC: 0 AN: 9924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2992

East Asian (EAS) AF: 0.000809 AC: 3 AN: 3710

South Asian (SAS) AF: 0.00 AC: 0 AN: 2974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54474

Other (OTH) AF: 0.00 AC: 0 AN: 1386

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Benign:2

Oct 23, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Uncertain:1

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a deletion of four nucleotides at the -4 position in intron 20 of the TSC1 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Benign:1

Aug 04, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 20, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48
Mutation Taster		=91/9	polymorphism

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: COSV109425221;