9-132905878-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000368.5(TSC1):​c.1700C>G​(p.Ala567Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A567V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC1
NM_000368.5 missense

Scores

7
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.18
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.351598).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.1700C>G p.Ala567Gly missense_variant Exon 15 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.1700C>G p.Ala567Gly missense_variant Exon 15 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.1700C>G p.Ala567Gly missense_variant Exon 16 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.042
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
15
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T;.;T;.;.;T;.;T;.;.;.
Eigen
Benign
0.10
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.89
.;D;D;D;D;.;.;.;D;D;.
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.35
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.060
T
MutationAssessor
Benign
1.8
L;.;L;.;.;L;.;L;.;.;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.1
N;N;N;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.32
Sift
Benign
0.16
T;T;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.44
T;T;T;.;.;.;.;.;.;.;.
Polyphen
0.77
P;.;P;.;.;P;.;P;.;.;.
Vest4
0.56
MutPred
0.63
Loss of catalytic residue at A567 (P = 0.0135);.;Loss of catalytic residue at A567 (P = 0.0135);.;.;Loss of catalytic residue at A567 (P = 0.0135);.;Loss of catalytic residue at A567 (P = 0.0135);.;Loss of catalytic residue at A567 (P = 0.0135);.;
MVP
0.85
MPC
0.52
ClinPred
0.66
D
GERP RS
4.0
Varity_R
0.078
gMVP
0.22

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: chr9-135781265; API