Genetic Variant TSC1:p.Arg509Gln (chr9-132906052-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000368.5(TSC1):c.1526G>A(p.Arg509Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,038 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R509L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:2

Conservation

PhyloP100: 0.660

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01075694).

BP6

Variant 9-132906052-C-T is Benign according to our data. Variant chr9-132906052-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000631 (96/152222) while in subpopulation AFR AF = 0.00224 (93/41548). AF 95% confidence interval is 0.00187. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 96 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC1	NM_000368.5	MANE Select	c.1526G>A	p.Arg509Gln	missense	Exon 15 of 23	NP_000359.1
TSC1	NM_001406592.1		c.1526G>A	p.Arg509Gln	missense	Exon 15 of 23	NP_001393521.1
TSC1	NM_001406593.1		c.1526G>A	p.Arg509Gln	missense	Exon 15 of 23	NP_001393522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1526G>A	p.Arg509Gln	missense	Exon 15 of 23	ENSP00000298552.3
TSC1	ENST00000490179.4	TSL:3	c.1526G>A	p.Arg509Gln	missense	Exon 16 of 24	ENSP00000495533.2
TSC1	ENST00000643875.1		c.1526G>A	p.Arg509Gln	missense	Exon 15 of 23	ENSP00000495158.1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD2 exomes

AF:

0.000156

AC:

AN:

250572

AF XY:

0.0000812

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.0000579

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:

0.000327

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

33474

American (AMR)

AF:

0.000112

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111996

Other (OTH)

AF:

0.000149

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000631

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41548

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000223

Hom.:

Bravo

AF:

0.000589

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Feb 08, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TSC1 c.1526G>A (p.Arg509Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 276324 control chromosomes, predominantly at a frequency of 0.002 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1526G>A has been reported in the literature in a child of African origin with multiple congenital malformations and no signs of Tuberous Sclerosis Complex (TSC); the variant was also identified in one of the parents (no signs of TSC). Experimental evidence evaluating an impact on protein function demonstrated the variant to display similar values to the wild type and be active in immunoblotting assay and to not affect TSC1 function (Hoogeveen-Westerveld_2011, Nellist_2009). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (2x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.

Sep 12, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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.

Aug 02, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tuberous sclerosis 1

Benign:3

Feb 04, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 23, 2023

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.

Hereditary cancer-predisposing syndrome

Benign:2

Dec 31, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Mar 22, 2018

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.

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1

Benign:1

Jul 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC1: BP4, BS1

Tuberous sclerosis syndrome

Other:1

Tuberous sclerosis database (TSC1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.82

M_CAP

Benign

0.058

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.77

PhyloP100

0.66

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.81

REVEL

Benign

0.20

Sift

Benign

0.072

Sift4G

Benign

0.64

Polyphen

0.011

Vest4

0.25

MVP

0.61

MPC

0.59

ClinPred

0.0071

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.048

gMVP

0.21

Mutation Taster

=84/16

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over