rs118203576

chr9-132905818-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000368.5(TSC1):c.1760A>G(p.Lys587Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00671 in 1,614,146 control chromosomes in the GnomAD database, including 890 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K587E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (138 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (752 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:22 O:2
• Conservation: PhyloP100: 4.50

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 -17 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132905817-T-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017258227).
• BP6: Variant 9-132905818-T-C is Benign according to our data. Variant chr9-132905818-T-C is described in ClinVar as [Benign]. Clinvar id is 5099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905818-T-C is described in Lovd as [Likely_benign]. Variant chr9-132905818-T-C is described in Lovd as [Benign]. Variant chr9-132905818-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1760A>G	p.Lys587Arg	missense_variant	15/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1760A>G	p.Lys587Arg	missense_variant	15/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2052 AN: 152150 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0260 AC: 6526 AN: 251104 Hom.: 621 AF XY: 0.0198 AC XY: 2681 AN XY: 135700

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.00600 AC: 8768 AN: 1461878 Hom.: 752 Cov.: 31 AF XY: 0.00515 AC XY: 3743 AN XY: 727238

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.0135 AC: 2062 AN: 152268 Hom.: 138 Cov.: 32 AF XY: 0.0153 AC XY: 1137 AN XY: 74450

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.00176 Hom.: 21

Bravo AF: 0.0210

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0188 AC: 2278

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:22 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2021	Variant summary: TSC1 c.1760A>G (p.Lys587Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 252466 control chromosomes, predominantly at a frequency of 0.17 within the Latino subpopulation in the gnomAD database, including 614 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6,800-fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. c.1760A>G has been reported in the literature in Tuberous Sclerosis Complex patients with other known causal variants (e.g. TSC2 c.648+1G>A; van Slegtenhorst_1997), providing supporting evidence for a benign role. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2012	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	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Tuberous sclerosis 1 Uncertain:1 Benign:7

Benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 07, 2015	- -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Tuberous sclerosis syndrome 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.70	A;A;A;A
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.71	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.045	D;T;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.59	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.010	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.23
MPC		0.49
ClinPred		0.016	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.17

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: rs118203576; hg19: chr9-135781205; COSMIC: COSV53769494; COSMIC: COSV53769494;