9-132896571-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000368.5(TSC1):​c.3159C>G​(p.His1053Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.055534363).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.3159C>G p.His1053Gln missense_variant Exon 23 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.3159C>G p.His1053Gln missense_variant Exon 23 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.3159C>G p.His1053Gln missense_variant Exon 24 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251212
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135812
show subpopulations
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461770
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
15
DANN
Benign
0.40
DEOGEN2
Benign
0.31
T;.;T;.;.;T;.;T;.;.;.
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.71
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.55
.;T;T;T;T;.;.;.;T;T;.
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.056
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
0.0
N;.;N;.;.;N;.;N;.;.;.
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.050
N;N;N;.;.;.;.;.;.;.;.
REVEL
Benign
0.25
Sift
Benign
0.26
T;T;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.59
T;T;T;.;.;.;.;.;.;.;.
Polyphen
0.011
B;.;B;.;.;B;.;B;.;.;.
Vest4
0.048
MutPred
0.098
Gain of solvent accessibility (P = 0.0155);.;Gain of solvent accessibility (P = 0.0155);.;.;Gain of solvent accessibility (P = 0.0155);.;Gain of solvent accessibility (P = 0.0155);.;.;.;
MVP
0.58
MPC
0.52
ClinPred
0.017
T
GERP RS
3.6
Varity_R
0.030
gMVP
0.098

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778413037; hg19: chr9-135771958; API