rs35593170

Positions:

• chr9-132896406-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000368.5(TSC1):​c.3324C>T​(p.Gly1108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,196 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (391 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:2
• Conservation: PhyloP100: -0.0670

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-132896406-G-A is Benign according to our data. Variant chr9-132896406-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 49024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132896406-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.067 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.3324C>T	p.Gly1108=	synonymous_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.3324C>T	p.Gly1108=	synonymous_variant	23/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1109 AN: 152186 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0184 AC: 4618 AN: 251428 Hom.: 323 AF XY: 0.0143 AC XY: 1940 AN XY: 135896

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00304

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.000879

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00421 AC: 6156 AN: 1461892 Hom.: 391 Cov.: 31 AF XY: 0.00368 AC XY: 2674 AN XY: 727246

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00406

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00232

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.00729 AC: 1110 AN: 152304 Hom.: 48 Cov.: 32 AF XY: 0.00855 AC XY: 637 AN XY: 74468

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0621

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00217 Hom.: 5

Bravo AF: 0.0128

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 19. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 16, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Tuberous sclerosis 1 Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 17, 2022	- -

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.3324C>T (p.Gly1108Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict the variant to result in the creation of a cyrpitc splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1690/121388 control chromosomes (132 homozygotes), predominantly observed in the Latino subpopulation at a frequency of 0.1302506 (1507/11570). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), strong evidence that this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

Tuberous sclerosis syndrome Benign:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2014

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. -

Malignant tumor of urinary bladder Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35593170; hg19: chr9-135771793; COSMIC: COSV53764062; COSMIC: COSV53764062;