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rs750441497

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PP2PP3_ModerateBP6

The NM_000368.5(TSC1):​c.110G>C​(p.Arg37Pro) 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. Variant has been reported in Lovd as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TSC1
NM_000368.5 missense

Scores

11
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.65
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 Likely_pathogenic. Variant got 6 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_000368.5
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, TSC1
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.92
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 9-132927301-C-G is Benign according to our data. Variant chr9-132927301-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSC1NM_000368.5 linkuse as main transcriptc.110G>C p.Arg37Pro missense_variant 4/23 ENST00000298552.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSC1ENST00000298552.9 linkuse as main transcriptc.110G>C p.Arg37Pro missense_variant 4/231 NM_000368.5 P4Q92574-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Uncertain
2.5
M;M;M;.;M;.;M;.;.;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-4.1
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0020
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Sift4G
Uncertain
0.0040
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen
1.0
D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.;.
Vest4
0.92
MutPred
0.76
Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP
0.92
MPC
1.7
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.86
gMVP
0.82

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: chr9-135802688; API