NM_000368.5:c.878C>T

Variant names:

• chr9-132912317-G-A
• rs756681916
• NM_000368.5:c.878C>T

Variant summary

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

The NM_000368.5(TSC1):​c.878C>T​(p.Thr293Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.98

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=0.31844735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.878C>T	p.Thr293Ile	missense_variant	Exon 9 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.878C>T	p.Thr293Ile	missense_variant	Exon 9 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.878C>T	p.Thr293Ile	missense_variant	Exon 10 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251336 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 1 Uncertain:1

Jan 28, 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 missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 934031). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is present in population databases (rs756681916, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 293 of the TSC1 protein (p.Thr293Ile). -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T293I variant (also known as c.878C>T), located in coding exon 7 of the TSC1 gene, results from a C to T substitution at nucleotide position 878. The threonine at codon 293 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.12
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Benign	-0.078
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.2	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.010	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.025	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		0.0010	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.
Vest4		0.19
MutPred		0.65		Loss of glycosylation at T293 (P = 0.0129);.;Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);.;.;Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);.;Loss of glycosylation at T293 (P = 0.0129);.;
MVP		0.62
MPC		0.54
ClinPred		0.49	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs756681916; hg19: chr9-135787704;