9-132902721-C-T

Position:

• chr9-132902721-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000368.5(TSC1):​c.2275G>A​(p.Ala759Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,840 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.51

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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13537642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2275G>A	p.Ala759Thr	missense_variant	18/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2275G>A	p.Ala759Thr	missense_variant	18/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 06, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 759 of the TSC1 protein (p.Ala759Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 411221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The p.A759T variant (also known as c.2275G>A), located in coding exon 16 of the TSC1 gene, results from a G to A substitution at nucleotide position 2275. The alanine at codon 759 is replaced by threonine, 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. 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	0.080
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.55	N;.;N;.;.;N;.;N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.33	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.54	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.58	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.61	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.29
MutPred		0.084		Gain of phosphorylation at A759 (P = 0.0373);.;Gain of phosphorylation at A759 (P = 0.0373);.;.;Gain of phosphorylation at A759 (P = 0.0373);.;Gain of phosphorylation at A759 (P = 0.0373);.;.;.;
MVP		0.70
MPC		0.48
ClinPred		0.40	T
GERP RS		5.7
Varity_R		0.043
gMVP		0.11

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: rs1060503199; hg19: chr9-135778108;