9-132921376-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000368.5(TSC1):​c.724C>A​(p.Leu242Met) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L242P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC1
NM_000368.5 missense

Scores

7
8
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.99
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
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000368.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSC1NM_000368.5 linkuse as main transcriptc.724C>A p.Leu242Met missense_variant 8/23 ENST00000298552.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSC1ENST00000298552.9 linkuse as main transcriptc.724C>A p.Leu242Met missense_variant 8/231 NM_000368.5 P4Q92574-1

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
0.27
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;T;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D
M_CAP
Benign
0.073
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.5
M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.83
N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL
Pathogenic
0.70
Sift
Uncertain
0.011
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G
Uncertain
0.011
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen
1.0
D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.
Vest4
0.53
MutPred
0.64
Gain of MoRF binding (P = 0.0826);.;Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);.;.;Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);.;Gain of MoRF binding (P = 0.0826);.;
MVP
0.74
MPC
1.2
ClinPred
0.89
D
GERP RS
6.0
Varity_R
0.33
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: chr9-135796763; API