9-132901668-G-T

Variant summary

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

The NM_000368.5(TSC1):​c.2423C>A​(p.Ala808Glu) 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. 15/21 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. A808V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC1
NM_000368.5 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.47
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=0.09240219).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.2423C>A p.Ala808Glu missense_variant Exon 19 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.2423C>A p.Ala808Glu missense_variant Exon 19 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.2423C>A p.Ala808Glu missense_variant Exon 20 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
0.28
BayesDel_addAF
Uncertain
0.020
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
18
DANN
Benign
0.86
DEOGEN2
Benign
0.32
T;.;T;.;.;T;.;T;.;.;.
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.85
.;D;D;T;D;.;.;.;D;D;.
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.092
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
1.2
L;.;L;.;.;L;.;L;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.15
N;N;N;.;.;.;.;.;.;.;.
REVEL
Benign
0.20
Sift
Benign
0.72
T;T;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.59
T;T;T;.;.;.;.;.;.;.;.
Polyphen
0.80
P;.;P;.;.;P;.;P;.;.;.
Vest4
0.50
MutPred
0.25
Gain of disorder (P = 0.0188);.;Gain of disorder (P = 0.0188);.;.;Gain of disorder (P = 0.0188);.;Gain of disorder (P = 0.0188);.;.;.;
MVP
0.59
MPC
0.59
ClinPred
0.37
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.12
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: chr9-135777055; API