9-132903711-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000368.5(TSC1):​c.2148C>G​(p.Asn716Lys) variant causes a missense change. 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

TSC1
NM_000368.5 missense

Scores

8
10
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.71
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.2148C>G p.Asn716Lys missense_variant Exon 17 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.2148C>G p.Asn716Lys missense_variant Exon 17 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.2148C>G p.Asn716Lys missense_variant Exon 18 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
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.;D;.;.;D;.;D;.;.;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;.;.;.;D;D;.
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.5
M;.;M;.;.;M;.;M;.;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.5
D;D;D;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;D;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.028
D;D;D;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;D;.;.;D;.;D;.;.;.
Vest4
0.94
MutPred
0.80
Gain of methylation at N716 (P = 0.0275);.;Gain of methylation at N716 (P = 0.0275);.;.;Gain of methylation at N716 (P = 0.0275);.;Gain of methylation at N716 (P = 0.0275);.;.;.;
MVP
0.93
MPC
1.5
ClinPred
1.0
D
GERP RS
2.4
Varity_R
0.84
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr9-135779098; API