9-132928784-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000368.5(TSC1):c.89A>G(p.Lys30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K30K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 2.22

Publications

6 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
lung lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23860356).

BP6

Variant 9-132928784-T-C is Benign according to our data. Variant chr9-132928784-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207623.

BS2

High AC in GnomAdExome4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.89A>G	p.Lys30Arg	missense_variant	Exon 3 of 23	ENST00000298552.9	NP_000359.1	Q92574-1Q86WV8X5D9D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 link	c.89A>G	p.Lys30Arg	missense_variant	Exon 3 of 23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.89A>G	p.Lys30Arg	missense_variant	Exon 4 of 24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1111982

Other (OTH)

AF:

0.0000828

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000679

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28805986) -

Tuberous sclerosis 1

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis syndrome

Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces lysine with arginine at codon 30 of the TSC1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has been identified in 1/31406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

TSC1-related disorder

Benign:1

Sep 01, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 28, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

0.069

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.055

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T;T;T;T

M_CAP

Benign

0.054

MetaRNN

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

1.9

L;L;L;.;L;.;L;.;.;L;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

2.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.030

N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.35

T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.

Sift4G

Benign

0.68

T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.

Polyphen

0.23

B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.;.;.

Vest4

0.19

MutPred

0.62

Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);Loss of ubiquitination at K30 (P = 0.0092);

MVP

0.82

MPC

0.42

ClinPred

0.50

GERP RS

3.9

PromoterAI

-0.00080

Neutral

(source)

Varity_R

0.063

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over