rs397514808

Positions:

• chr9-132911475-C-A
• chr9-132911475-C-G
• chr9-132911475-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001406629.1(TSC1):​c.-87G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_001406629.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1007G>T	p.Arg336Leu	missense_variant	10/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1007G>T	p.Arg336Leu	missense_variant	10/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1007G>T	p.Arg336Leu	missense_variant	11/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The p.R336L variant (also known as c.1007G>T), located in coding exon 8 of the TSC1 gene, results from a G to T substitution at nucleotide position 1007. The arginine at codon 336 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;T
Eigen	Benign	0.018
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.8	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.055	T;D;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
Sift4G	Benign	0.12	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.011	B;.;B;.;B;.;B;.;.;.;.;P;P;P;.;.;.;B
Vest4		0.60
MutPred		0.60		Loss of phosphorylation at T339 (P = 0.0546);.;Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);.;.;Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);Loss of phosphorylation at T339 (P = 0.0546);.;Loss of phosphorylation at T339 (P = 0.0546);
MVP		0.92
MPC		0.63
ClinPred		0.65	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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: chr9-135786862;