rs397515167

chr16-2084955-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000548.5(TSC2):c.4498G>A(p.Val1500Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1500L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 9.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000548.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2084956-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4498G>A	p.Val1500Met	missense_variant	35/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4498G>A	p.Val1500Met	missense_variant	35/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250308 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460968 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 726804

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2023	The p.V1500M variant (also known as c.4498G>A), located in coding exon 34 of the TSC2 gene, results from a G to A substitution at nucleotide position 4498. The valine at codon 1500 is replaced by methionine, an amino acid with highly similar properties. In one functional study, this alteration was classified as probably neutral as it did not appear to impact inhibition of TORC1 (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 16, 2017

- -

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 19, 2023

This missense variant replaces valine with methionine at codon 1500 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies demonstrated no effect on TSC1 or TSC2 protein abundance, or on TSC1-TSC2 dependent inhibition of TORC1 activity (PMID: 22903760). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250308 chromosomes 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 syndrome;C0751674:Lymphangiomyomatosis Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.88
MutPred		0.43		Loss of catalytic residue at V1500 (P = 0.0063);.;.;.;.;.;.;Loss of catalytic residue at V1500 (P = 0.0063);.;.;.;.;.;.;.;
MVP		0.95
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs397515167; hg19: chr16-2134956; COSMIC: COSV51918475; COSMIC: COSV51918475;