9-132897613-GAAAAAA-GAAAAA

Position:

• chr9-132897613-GAAAAAA-GAAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000368.5(TSC1):​c.2626-4delT variant causes a splice region, 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.058 (147 hom., cov: 0)
  • Exomes 𝑓: 0.11 (18 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12 O:1
• 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]

TSC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 9-132897613-GA-G is Benign according to our data. Variant chr9-132897613-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48983.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Benign=10}. Variant chr9-132897613-GA-G is described in Lovd as [Benign]. Variant chr9-132897613-GA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-4delT		splice_region_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.2626-4delT		splice_region_variant, intron_variant		1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-4delT		splice_region_variant, intron_variant		3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 6083 AN: 104014 Hom.: 147 Cov.: 0

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.0667

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.0856

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0590

GnomAD3 exomes AF: 0.210 AC: 21819 AN: 103824 Hom.: 0 AF XY: 0.208 AC XY: 11908 AN XY: 57384

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.107 AC: 128027 AN: 1199362 Hom.: 18 Cov.: 0 AF XY: 0.107 AC XY: 63386 AN XY: 594370

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.0999

Gnomad4 SAS exome AF: 0.0811

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.0585 AC: 6080 AN: 104014 Hom.: 147 Cov.: 0 AF XY: 0.0581 AC XY: 2818 AN XY: 48544

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.0514

Gnomad4 ASJ AF: 0.0821

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0347

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.0633

Gnomad4 OTH AF: 0.0607

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	Population allele frequency is 19% (rs118203716, 22,767/119,574 alleles in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria is met: BA1. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Tuberous sclerosis syndrome Uncertain:1 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -
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.2626-4delT variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 22671/80186 (1 homozygote, 1/3, frequency: 0.2827302), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC1 variant of 1/40000(0.000025), suggesting this variant is likely a benign polymorphism. Therefore, the variant of interest has been classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -
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. -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;