9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-132897613-G-GAAAAAAA
• rs5901000
• NM_000368.5:c.2626-10_2626-4dupTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000368.5(TSC1):​c.2626-10_2626-4dupTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B: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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 9-132897613-G-GAAAAAAA is Benign according to our data. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132897613-G-GAAAAAAA is described in CliVar as Benign. Clinvar id is 1692400.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-10_2626-4dupTTTTTTT		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_2626-3insTTTTTTT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-4_2626-3insTTTTTTT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.00000960 AC: 1 AN: 104132 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000184

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000439 AC: 55 AN: 1253866 Hom.: 0 Cov.: 0 AF XY: 0.0000385 AC XY: 24 AN XY: 623200

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

African (AFR) AF: 0.00 AC: 0 AN: 28214

American (AMR) AF: 0.000110 AC: 3 AN: 27250

Ashkenazi Jewish (ASJ) AF: 0.0000495 AC: 1 AN: 20212

East Asian (EAS) AF: 0.0000846 AC: 3 AN: 35452

South Asian (SAS) AF: 0.0000914 AC: 6 AN: 65640

European-Finnish (FIN) AF: 0.0000603 AC: 2 AN: 33146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.0000395 AC: 39 AN: 987626

Other (OTH) AF: 0.0000193 AC: 1 AN: 51762

⚠️ 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: 0.00000960 AC: 1 AN: 104132 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 48576

African (AFR) AF: 0.00 AC: 0 AN: 24100

American (AMR) AF: 0.00 AC: 0 AN: 9916

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3722

South Asian (SAS) AF: 0.00 AC: 0 AN: 2988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000184 AC: 1 AN: 54476

Other (OTH) AF: 0.00 AC: 0 AN: 1374

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Aug 17, 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		-0.52

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;