rs118203543

Variant names:

• chr9-132906052-C-A
• NM_000368.5:c.1526G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132906052-C-A
• chr9-132906052-C-G
• chr9-132906052-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000368.5(TSC1):​c.1526G>T​(p.Arg509Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R509Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.660

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132906052-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1526G>T	p.Arg509Leu	missense_variant	Exon 15 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1526G>T	p.Arg509Leu	missense_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1526G>T	p.Arg509Leu	missense_variant	Exon 16 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Nov 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function. This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 509 of the TSC1 protein (p.Arg509Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D;.;D;.;.;D;.;D;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.033	D;T;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.67	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.0050	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.43
MutPred		0.60		Loss of phosphorylation at S511 (P = 0.0641);.;Loss of phosphorylation at S511 (P = 0.0641);.;.;Loss of phosphorylation at S511 (P = 0.0641);.;Loss of phosphorylation at S511 (P = 0.0641);.;Loss of phosphorylation at S511 (P = 0.0641);.;
MVP		0.41
MPC		0.64
ClinPred		0.53	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135781439; COSMIC: COSV100051589; COSMIC: COSV100051589;