rs1060503214

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-132896671-G-A
• chr9-132896671-G-C
• chr9-132896671-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000368.5(TSC1):​c.3059C>T​(p.Thr1020Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.74

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1054779).
• BP6: Variant 9-132896671-G-A is Benign according to our data. Variant chr9-132896671-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411259.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.3059C>T	p.Thr1020Ile	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>T	p.Thr1020Ile	missense_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.3059C>T	p.Thr1020Ile	missense_variant	Exon 24 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1020I variant (also known as c.3059C>T), located in coding exon 21 of the TSC1 gene, results from a C to T substitution at nucleotide position 3059. The threonine at codon 1020 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species and isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated 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	0.077
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.7	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.77	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.071	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.23	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.047	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.027
MutPred		0.13		Loss of phosphorylation at T1020 (P = 0.005);.;Loss of phosphorylation at T1020 (P = 0.005);.;.;Loss of phosphorylation at T1020 (P = 0.005);.;Loss of phosphorylation at T1020 (P = 0.005);.;.;.;
MVP		0.26
MPC		0.54
ClinPred		0.31	T
GERP RS		3.2
Varity_R		0.030
gMVP		0.26

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: rs1060503214; hg19: chr9-135772058;