Genetic Variant NM_000368.5:c.-129A>T (chr9-132935081-T-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000368.5(TSC1):c.-129A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 399,072 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 24 hom., cov: 33)

Exomes 𝑓: 0.014 ( 27 hom. )

Consequence

TSC1
NM_000368.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.394

Publications

0 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 9-132935081-T-A is Benign according to our data. Variant chr9-132935081-T-A is described in ClinVar as Benign. ClinVar VariationId is 64720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0118 (1796/152328) while in subpopulation AMR AF = 0.0196 (300/15304). AF 95% confidence interval is 0.0178. There are 24 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1796 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	Effect	Exon Rank	Protein
TSC1	NM_000368.5	MANE Select	c.-129A>T	5_prime_UTR	Exon 2 of 23	NP_000359.1
TSC1	NR_176214.1		n.89A>T	non_coding_transcript_exon	Exon 2 of 22
TSC1	NR_176215.1		n.89A>T	non_coding_transcript_exon	Exon 2 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.-129A>T	5_prime_UTR	Exon 2 of 23	ENSP00000298552.3
TSC1	ENST00000490179.4	TSL:3	c.-225A>T	5_prime_UTR	Exon 2 of 24	ENSP00000495533.2
TSC1	ENST00000403810.6	TSL:1	c.-129A>T	5_prime_UTR	Exon 2 of 10	ENSP00000386093.1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1796

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0201

GnomAD4 exome

AF:

0.0136

AC:

3352

AN:

246744

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1733

AN XY:

125064

show subpopulations

African (AFR)

AF:

0.00237

AC:

AN:

7180

American (AMR)

AF:

0.0143

AC:

106

AN:

7434

Ashkenazi Jewish (ASJ)

AF:

0.0226

AC:

209

AN:

9240

East Asian (EAS)

AF:

0.00

AC:

AN:

22894

South Asian (SAS)

AF:

0.000660

AC:

AN:

3032

European-Finnish (FIN)

AF:

0.00527

AC:

112

AN:

21254

Middle Eastern (MID)

AF:

0.0193

AC:

AN:

1294

European-Non Finnish (NFE)

AF:

0.0168

AC:

2657

AN:

158040

Other (OTH)

AF:

0.0137

AC:

224

AN:

16376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

168

336

504

672

840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0118

AC:

1796

AN:

152328

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

833

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41576

American (AMR)

AF:

0.0196

AC:

300

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1094

AN:

68028

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0107

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tuberous sclerosis syndrome

Benign:1Other:1

Jun 16, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tuberous sclerosis database (TSC1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Tuberous sclerosis 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Isolated focal cortical dysplasia type II

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.39

PromoterAI

-0.00090

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Mutation Taster

=297/3

polymorphism

(source)

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

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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