9-132905635-A-T

Variant summary

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

The NM_000368.5(TSC1):​c.1943T>A​(p.Val648Glu) variant causes a missense change involving the alteration of a 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

TSC1
NM_000368.5 missense

Scores

10
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.10
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, 0.91

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.1943T>A p.Val648Glu 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.1943T>A p.Val648Glu missense_variant Exon 15 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.1943T>A p.Val648Glu 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
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
D;.;D;.;.;D;.;D;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.89
.;D;D;D;D;.;.;.;D;D;.
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Uncertain
2.5
M;.;M;.;.;M;.;M;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-4.0
D;D;D;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;D;D;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;D;.;.;D;.;D;.;.;.
Vest4
0.94
MutPred
0.78
Gain of disorder (P = 0.0058);.;Gain of disorder (P = 0.0058);.;.;Gain of disorder (P = 0.0058);.;Gain of disorder (P = 0.0058);.;Gain of disorder (P = 0.0058);.;
MVP
0.88
MPC
1.7
ClinPred
0.99
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.82
gMVP
0.77

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: chr9-135781022; API