9-132912314-G-C

Position:

• chr9-132912314-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000368.5(TSC1):​c.881C>G​(p.Thr294Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.280604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.881C>G	p.Thr294Ser	missense_variant	9/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.881C>G	p.Thr294Ser	missense_variant	9/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.881C>G	p.Thr294Ser	missense_variant	10/24	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

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The p.T294S variant (also known as c.881C>G), located in coding exon 7 of the TSC1 gene, results from a C to G substitution at nucleotide position 881. The threonine at codon 294 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.39	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	-0.099
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.52	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.14	N;.;N;.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.48	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.76	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Sift4G	Benign	1.0	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Polyphen		0.0	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.
Vest4		0.14
MutPred		0.48		Loss of catalytic residue at T294 (P = 0.0525);.;Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);.;.;Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);Loss of catalytic residue at T294 (P = 0.0525);.;Loss of catalytic residue at T294 (P = 0.0525);.;
MVP		0.60
MPC		0.45
ClinPred		0.79	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr9-135787701;