NM_000368.5:c.3059C>G

Variant names:

• chr9-132896671-G-C
• rs1060503214
• NM_000368.5:c.3059C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000368.5(TSC1):​c.3059C>G​(p.Thr1020Ser) 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. 17/22 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. T1020I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066061854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.3059C>G	p.Thr1020Ser	missense_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.3059C>G	p.Thr1020Ser	missense_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.3059C>G	p.Thr1020Ser	missense_variant	Exon 24 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with serine at codon 1020 of the TSC1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1020S variant (also known as c.3059C>G), located in coding exon 21 of the TSC1 gene, results from a C to G substitution at nucleotide position 3059. The threonine at codon 1020 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	0.082
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.69
DEOGEN2	Benign	0.33	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.066	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L;.;L;.;.;L;.;L;.;.;.
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.75	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.71	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.82	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.039	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.053
MutPred		0.14		Loss of glycosylation at T1020 (P = 0.0424);.;Loss of glycosylation at T1020 (P = 0.0424);.;.;Loss of glycosylation at T1020 (P = 0.0424);.;Loss of glycosylation at T1020 (P = 0.0424);.;.;.;
MVP		0.25
MPC		0.46
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.021
gMVP		0.18
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1060503214; hg19: chr9-135772058;