9-132896627-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000368.5(TSC1):​c.3103G>A​(p.Gly1035Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,806 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0021 ( 6 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17O:2

Conservation

PhyloP100: 0.846
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 Benign. Variant got -12 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=0.005901724).
BP6
Variant 9-132896627-C-T is Benign according to our data. Variant chr9-132896627-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41696.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, not_provided=2, Benign=10}. Variant chr9-132896627-C-T is described in Lovd as [Likely_benign]. Variant chr9-132896627-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152252) while in subpopulation NFE AF= 0.00215 (146/68016). AF 95% confidence interval is 0.00186. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 210 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC1NM_000368.5 linkuse as main transcriptc.3103G>A p.Gly1035Ser 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.3103G>A p.Gly1035Ser missense_variant 23/231 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkuse as main transcriptc.3103G>A p.Gly1035Ser missense_variant 24/243 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
AF:
0.00138
AC:
210
AN:
152132
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00215
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00139
AC:
348
AN:
249584
Hom.:
1
AF XY:
0.00126
AC XY:
170
AN XY:
135288
show subpopulations
Gnomad AFR exome
AF:
0.000255
Gnomad AMR exome
AF:
0.00174
Gnomad ASJ exome
AF:
0.00379
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000232
Gnomad NFE exome
AF:
0.00201
Gnomad OTH exome
AF:
0.00214
GnomAD4 exome
AF:
0.00214
AC:
3126
AN:
1461554
Hom.:
6
Cov.:
31
AF XY:
0.00209
AC XY:
1520
AN XY:
727062
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.00150
Gnomad4 ASJ exome
AF:
0.00279
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.000244
Gnomad4 NFE exome
AF:
0.00255
Gnomad4 OTH exome
AF:
0.00205
GnomAD4 genome
AF:
0.00138
AC:
210
AN:
152252
Hom.:
1
Cov.:
32
AF XY:
0.00124
AC XY:
92
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.000554
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00231
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00215
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00209
Hom.:
2
Bravo
AF:
0.00156
TwinsUK
AF:
0.00270
AC:
10
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00186
AC:
16
ExAC
AF:
0.00140
AC:
170
EpiCase
AF:
0.00289
EpiControl
AF:
0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:17Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:6Other:1
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 04, 2015- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoAug 25, 2021- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 01, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 19, 2021- -
not provided Uncertain:1Benign:4
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 26, 2023- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024TSC1: BP4, BS1 -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 31, 2016Variant Summary: The c.3103G>A (p.Gly1035Ser) in TSC1 gene is a missense change that involves a non-conserved nucleotide and 3/4 in silico programs predicting a "benign" outcome. The variant of interest was observed in controls with an allele frequency of 0.0014 (170/119052chrs tested) which exceeds the predicted maximum expected allele frequency for a pathogenic variant in this gene (0.0025). The variant of interest has been reported in multiple affected individuals in cis with a pathogenic variant (Nellist, 2009, TSC1 db).In the functional studies the G1035S had similar activities as wt (Nellist, 2009). In addition, multiple reputable databases/clinical laboratories and publications cite the variant with a classification of "Neutral/likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a Benign. -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Likely benign, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Tuberous sclerosis 1 Benign:4
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 09, 2022- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 25, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 03, 2014This alteration is classified as 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. -
Benign, criteria provided, single submittercurationSema4, Sema4Sep 24, 2020- -
Isolated focal cortical dysplasia type II Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 25, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Tuberous sclerosis syndrome Other:1
not provided, no classification providedcurationTuberous sclerosis database (TSC1)-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
13
DANN
Benign
0.93
DEOGEN2
Benign
0.29
T;.;T;.;.;T;.;T;.;.;.
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.68
.;T;T;T;T;.;.;.;T;T;.
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.0059
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
1.9
M;.;M;.;.;M;.;M;.;.;.
PrimateAI
Benign
0.29
T
PROVEAN
Benign
0.70
N;N;N;.;.;.;.;.;.;.;.
REVEL
Benign
0.17
Sift
Benign
0.17
T;T;T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.75
T;T;T;.;.;.;.;.;.;.;.
Polyphen
0.044
B;.;B;.;.;B;.;B;.;.;.
Vest4
0.11
MVP
0.75
MPC
0.50
ClinPred
0.0073
T
GERP RS
4.3
Varity_R
0.020
gMVP
0.15

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: rs118203742; hg19: chr9-135772014; COSMIC: COSV53772381; COSMIC: COSV53772381; API