chr9-132911004-G-A

Position:

• chr9-132911004-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000368.5(TSC1):​c.1139C>T​(p.Thr380Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1139C>T	p.Thr380Ile	missense_variant, splice_region_variant	Exon 11 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1139C>T	p.Thr380Ile	missense_variant, splice_region_variant	Exon 11 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1139C>T	p.Thr380Ile	missense_variant, splice_region_variant	Exon 12 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 380 of the TSC1 protein (p.Thr380Ile). 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: 534410). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.66	.;T;T;T;.;.;.;T;T;.;.;.;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.50	D;D;D;T;D;T;D;T;D;D;D;D;D;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.9	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.043	D;T;D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.066	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.15	B;.;B;.;B;.;B;.;.;.;B;B;B;.;.
Vest4		0.18
MutPred		0.52		Loss of glycosylation at T380 (P = 0.0093);.;Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);.;Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);Loss of glycosylation at T380 (P = 0.0093);.;
MVP		0.55
MPC		0.85
ClinPred		0.76	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.12		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: rs1064796512; hg19: chr9-135786391;