9-132897613-G-GA

Position:

• chr9-132897613-G-GA

Variant summary

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

The ENST00000298552.9(TSC1):​c.2626-4_2626-3insT variant causes a splice region, splice polypyrimidine tract, 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 ENST00000298552.9 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• 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-GA is Benign according to our data. Variant chr9-132897613-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

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

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

GnomAD3 exomes AF: 0.170 AC: 17641 AN: 103824 Hom.: 883 AF XY: 0.173 AC XY: 9924 AN XY: 57384

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 SAS exome AF: 0.191

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

Gnomad4 AFR exome AF: 0.0980

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.00816 AC: 849 AN: 104078 Hom.: 26 Cov.: 0 AF XY: 0.00842 AC XY: 409 AN XY: 48572

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00696

Gnomad4 ASJ AF: 0.00267

Gnomad4 EAS AF: 0.00944

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.00277

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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)	-	- -

Tuberous sclerosis 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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 provided Benign:2

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.2626-4dupT 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2019	This variant is associated with the following publications: (PMID: 29849115) -

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	Feb 24, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;