chr9-132905683-T-C

Position:

• chr9-132905683-T-C

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.1895A>G​(p.Lys632Arg) 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. 14/21 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. K632E) has been classified as Uncertain significance.

• 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: 2.87

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=0.21918282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1895A>G	p.Lys632Arg	missense_variant	15/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1895A>G	p.Lys632Arg	missense_variant	15/23	1	NM_000368.5	P4

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 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 27, 2017

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TSC1-related disease. This sequence change replaces lysine with arginine at codon 632 of the TSC1 protein (p.Lys632Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2023

The p.K632R variant (also known as c.1895A>G), located in coding exon 13 of the TSC1 gene, results from an A to G substitution at nucleotide position 1895. The lysine at codon 632 is replaced by arginine, an amino acid with highly 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	0.067
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.8	L;.;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.21	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.17	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.75	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.20
MutPred		0.42		Loss of ubiquitination at K632 (P = 0.0233);.;Loss of ubiquitination at K632 (P = 0.0233);.;.;Loss of ubiquitination at K632 (P = 0.0233);.;Loss of ubiquitination at K632 (P = 0.0233);.;Loss of ubiquitination at K632 (P = 0.0233);.;
MVP		0.76
MPC		0.41
ClinPred		0.42	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1554815747; hg19: chr9-135781070;