chr9-132911565-C-T

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.917G>A(p.Cys306Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 1,472,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C306R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.112

Publications

1 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=0.11152014).

BP6

Variant 9-132911565-C-T is Benign according to our data. Variant chr9-132911565-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466161.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.917G>A	p.Cys306Tyr	missense_variant	Exon 10 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.917G>A	p.Cys306Tyr	missense_variant	Exon 10 of 23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.917G>A	p.Cys306Tyr	missense_variant	Exon 11 of 24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.0000225

AC:

AN:

133284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000546

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250906

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000523

AC:

AN:

1339598

Hom.:

Cov.:

AF XY:

0.00000751

AC XY:

AN XY:

665774

show subpopulations

African (AFR)

AF:

0.000164

AC:

AN:

30404

American (AMR)

AF:

0.0000243

AC:

AN:

41218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22096

East Asian (EAS)

AF:

0.00

AC:

AN:

29458

South Asian (SAS)

AF:

0.00

AC:

AN:

84940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4718

European-Non Finnish (NFE)

AF:

9.72e-7

AC:

AN:

1028848

Other (OTH)

AF:

0.00

AC:

AN:

52846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000225

AC:

AN:

133284

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

62874

show subpopulations

African (AFR)

AF:

0.0000556

AC:

AN:

35958

American (AMR)

AF:

0.00

AC:

AN:

11534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.00

AC:

AN:

4028

South Asian (SAS)

AF:

0.00

AC:

AN:

3958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64870

Other (OTH)

AF:

0.000546

AC:

AN:

1830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000533

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Mar 08, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 11, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Jun 03, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PP2 -

Tuberous sclerosis 1

Uncertain:1Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 30, 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

0.073

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Uncertain

0.44

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

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.81

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

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.0

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

PhyloP100

-0.11

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.50

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

REVEL

Uncertain

0.46

Sift

Benign

0.18

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

Sift4G

Uncertain

0.041

D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.

Polyphen

0.032

B;.;B;.;B;.;B;.;.;.;.;P;P;P;.;.;.;P;.

Vest4

0.20

MutPred

0.38

Gain of phosphorylation at C306 (P = 0.0403);.;Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);.;.;Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);Gain of phosphorylation at C306 (P = 0.0403);.;Gain of phosphorylation at C306 (P = 0.0403);.;

MVP

0.49

MPC

1.2

ClinPred

0.19

GERP RS

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.35

Mutation Taster

=92/8

polymorphism

(source)

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

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chr9-132911565-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over