9-132897554-A-T

Variant summary

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

The NM_000368.5(TSC1):​c.2682T>A​(p.His894Gln) 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. 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: not found (cov: 31)

Consequence

TSC1
NM_000368.5 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0840
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=0.09532836).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.2682T>A p.His894Gln missense_variant Exon 21 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.2682T>A p.His894Gln missense_variant Exon 21 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.2682T>A p.His894Gln missense_variant Exon 22 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
3.3
DANN
Benign
0.85
DEOGEN2
Benign
0.29
T;.;T;.;.;T;.;T;.;.;.
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.66
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.55
.;T;T;T;T;.;.;.;T;T;.
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.095
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.0
N;.;N;.;.;N;.;N;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.86
N;N;N;.;.;.;.;.;.;.;.
REVEL
Benign
0.18
Sift
Benign
0.50
T;T;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.30
T;T;T;.;.;.;.;.;.;.;.
Polyphen
0.0
B;.;B;.;.;B;.;B;.;.;.
Vest4
0.27
MutPred
0.12
Loss of catalytic residue at L896 (P = 0.1042);.;Loss of catalytic residue at L896 (P = 0.1042);.;.;Loss of catalytic residue at L896 (P = 0.1042);.;Loss of catalytic residue at L896 (P = 0.1042);.;.;.;
MVP
0.54
MPC
0.50
ClinPred
0.14
T
GERP RS
-4.0
Varity_R
0.12
gMVP
0.032

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: chr9-135772941; API