rs148931779

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000368.5(TSC1):​c.3125G>T​(p.Ser1042Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

11
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.16519216).
BP6
Variant 9-132896605-C-A is Benign according to our data. Variant chr9-132896605-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207640.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC1NM_000368.5 linkuse as main transcriptc.3125G>T p.Ser1042Ile missense_variant 23/23 ENST00000298552.9 NP_000359.1 Q92574-1Q86WV8X5D9D2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC1ENST00000298552.9 linkuse as main transcriptc.3125G>T p.Ser1042Ile missense_variant 23/231 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkuse as main transcriptc.3125G>T p.Ser1042Ile missense_variant 24/243 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
249588
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135198
show subpopulations
Gnomad AFR exome
AF:
0.000380
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1461282
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
726874
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Tuberous sclerosis 1 Benign:3
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 15, 2024This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 24, 2017- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 15, 2019- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 29, 2018This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;.;T;.;.;T;.;T;.;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.86
.;D;D;D;D;.;.;.;D;D;.
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.17
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.064
T
MutationAssessor
Uncertain
2.3
M;.;M;.;.;M;.;M;.;.;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.1
N;N;N;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.39
Sift
Uncertain
0.0020
D;D;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.0020
D;D;D;.;.;.;.;.;.;.;.
Polyphen
0.97
D;.;D;.;.;D;.;D;.;.;.
Vest4
0.24
MVP
0.58
MPC
1.5
ClinPred
0.24
T
GERP RS
5.4
Varity_R
0.36
gMVP
0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148931779; hg19: chr9-135771992; API