rs7862221

Positions:

• chr9-132906834-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000368.5(TSC1):​c.1335A>G​(p.Glu445=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,436 control chromosomes in the GnomAD database, including 17,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. EE445G?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.16 (1966 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15107 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001175
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 0.929

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 9-132906834-T-C is Benign according to our data. Variant chr9-132906834-T-C is described in ClinVar as [Benign]. Clinvar id is 48768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906834-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.929 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1335A>G	p.Glu445=	splice_region_variant, synonymous_variant	14/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1335A>G	p.Glu445=	splice_region_variant, synonymous_variant	14/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23723 AN: 152046 Hom.: 1956 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0848

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.132 AC: 33147 AN: 250852 Hom.: 2331 AF XY: 0.131 AC XY: 17705 AN XY: 135606

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0877

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.141 AC: 206428 AN: 1461272 Hom.: 15107 Cov.: 32 AF XY: 0.140 AC XY: 101534 AN XY: 726910

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.0914

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.0711

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.156 AC: 23760 AN: 152164 Hom.: 1966 Cov.: 32 AF XY: 0.151 AC XY: 11201 AN XY: 74404

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0850

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.152

Alfa AF: 0.150 Hom.: 3049

Bravo AF: 0.158

Asia WGS AF: 0.128 AC: 449 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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)	Jul 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu445Glu in exon 14 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 21.9% (965/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs7862221). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Tuberous sclerosis 1 Benign:7

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	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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.1335A>G (p.Glu445Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change 2 nucleotides from the exon14-intron13 boundary. One in silico tool predicts a polymorphism outcome for this variant. 5/5 Alamut algorithms predict no significant change to the cononical splice acceptor site, while 2/5 predict a strengthening of a cryptic splice acceptor site. This variant was found in 16480/120190 control chromosomes (1225 homozygotes) at a frequency of 0.1371162, which is approximately 5485 times the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign, and it has been reported in the literature as a normal population variant (PMID: 18538015). Taken together and based on the high allele frequency in the general population, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.14		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: rs7862221; hg19: chr9-135782221; COSMIC: COSV53763241; COSMIC: COSV53763241;