rs1060500948

Positions:

• chr16-2080231-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.3464C>T​(p.Ser1155Phe) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.15

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity TSC2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19473931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3464C>T	p.Ser1155Phe	missense_variant	30/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3464C>T	p.Ser1155Phe	missense_variant	30/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

This missense variant replaces serine with phenylalanine at codon 1155 of the TSC2 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 TSC2-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. -

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2021

This sequence change replaces serine with phenylalanine at codon 1155 of the TSC2 protein (p.Ser1155Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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

Jan 04, 2021

The p.S1155F variant (also known as c.3464C>T), located in coding exon 29 of the TSC2 gene, results from a C to T substitution at nucleotide position 3464. The serine at codon 1155 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.097
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.027	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.61	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.44
MutPred		0.22		Loss of glycosylation at S1155 (P = 0.0122);.;Loss of glycosylation at S1155 (P = 0.0122);.;.;.;.;Loss of glycosylation at S1155 (P = 0.0122);.;Loss of glycosylation at S1155 (P = 0.0122);.;.;.;.;.;
MVP		0.78
ClinPred		0.12	T
GERP RS		2.5
Varity_R		0.061
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1060500948; hg19: chr16-2130232; COSMIC: COSV54770192; COSMIC: COSV54770192;