rs369046625

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001406689.1(TSC2):​c.-777C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC2
NM_001406689.1 5_prime_UTR_premature_start_codon_gain

Scores

4
12
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.655C>A p.Leu219Met missense_variant 8/42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.655C>A p.Leu219Met missense_variant 8/425 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 15, 2024The p.L219M variant (also known as c.655C>A), located in coding exon 7 of the TSC2 gene, results from a C to A substitution at nucleotide position 655. The leucine at codon 219 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.81
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.32
D
MutationAssessor
Uncertain
2.3
M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.8
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.010
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
1.0
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.82
MutPred
0.58
Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;
MVP
0.81
ClinPred
0.94
D
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.67
gMVP
0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2106651; API