9-132897613-G-GAA

Position:

• chr9-132897613-G-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.2626-4_2626-3insTT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (13696 hom., cov: 0)
  • Exomes 𝑓: 0.29 (4637 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.517

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-132897613-G-GAA is Benign according to our data. Variant chr9-132897613-G-GAA is described in ClinVar as [Benign]. Clinvar id is 495837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-4_2626-3insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-4_2626-3insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.525 AC: 54441 AN: 103658 Hom.: 13696 Cov.: 0

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.536

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.526

GnomAD3 exomes AF: 0.178 AC: 18478 AN: 103824 Hom.: 910 AF XY: 0.180 AC XY: 10307 AN XY: 57384

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.190

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.289 AC: 343152 AN: 1187976 Hom.: 4637 Cov.: 0 AF XY: 0.286 AC XY: 168350 AN XY: 589650

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.229

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.525 AC: 54438 AN: 103658 Hom.: 13696 Cov.: 0 AF XY: 0.527 AC XY: 25475 AN XY: 48328

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.558

Gnomad4 NFE AF: 0.585

Gnomad4 OTH AF: 0.525

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2016	Variant summary: The TSC1 c.2626-5_2626-4dupTT variant involves the duplication of two intronic nucleotides. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12290/80186 control chromosomes (278 homozygotes) at a frequency of 0.1532687, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic lab/reputable database classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2020	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;