9-132911485-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000368.5(TSC1):​c.997C>G​(p.Pro333Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Consequence

TSC1
NM_000368.5 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18542954).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.997C>G p.Pro333Ala missense_variant Exon 10 of 23 ENST00000298552.9 NP_000359.1 Q92574-1Q86WV8X5D9D2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC1ENST00000298552.9 linkc.997C>G p.Pro333Ala missense_variant Exon 10 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.997C>G p.Pro333Ala missense_variant Exon 11 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
20
DANN
Benign
0.89
DEOGEN2
Uncertain
0.45
T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;D
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.33
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.89
.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.19
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.8
L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.62
N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
REVEL
Uncertain
0.50
Sift
Benign
0.38
T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
Sift4G
Benign
0.77
T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen
0.071
B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B
Vest4
0.23
MutPred
0.47
Loss of glycosylation at P333 (P = 0.0148);.;Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);.;.;Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);Loss of glycosylation at P333 (P = 0.0148);.;Loss of glycosylation at P333 (P = 0.0148);
MVP
0.92
MPC
0.51
ClinPred
0.051
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.024
gMVP
0.16

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: chr9-135786872; API