Variant chr9-132897613-G-GAAA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_000368.5(TSC1):c.2626-6_2626-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 41 hom., cov: 0)

Exomes 𝑓: 0.047 ( 171 hom. )

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: -0.517

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 9-132897613-G-GAAA is Benign according to our data. Variant chr9-132897613-G-GAAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365514.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=1}.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.2626-6_2626-4dupTTT		splice_region_variant, intron_variant	Intron 20 of 22	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.2626-4_2626-3insTTT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.2626-4_2626-3insTTT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

1380

AN:

103968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.00139

Gnomad AMR

AF:

0.00686

Gnomad ASJ

AF:

0.000670

Gnomad EAS

AF:

0.00188

Gnomad SAS

AF:

0.00636

Gnomad FIN

AF:

0.00111

Gnomad MID

AF:

0.00450

Gnomad NFE

AF:

0.00971

Gnomad OTH

AF:

0.0160

GnomAD3 exomes

AF:

0.0565

AC:

5864

AN:

103824

Hom.:

AF XY:

0.0562

AC XY:

3223

AN XY:

57384

show subpopulations

Gnomad AFR exome

AF:

0.0337

Gnomad AMR exome

AF:

0.0651

Gnomad ASJ exome

AF:

0.0685

Gnomad EAS exome

AF:

0.0850

Gnomad SAS exome

AF:

0.0668

Gnomad FIN exome

AF:

0.0307

Gnomad NFE exome

AF:

0.0526

Gnomad OTH exome

AF:

0.0760

GnomAD4 exome

AF:

0.0469

AC:

57600

AN:

1229252

Hom.:

171

Cov.:

AF XY:

0.0468

AC XY:

28562

AN XY:

610466

show subpopulations

Gnomad4 AFR exome

AF:

0.0306

Gnomad4 AMR exome

AF:

0.0448

Gnomad4 ASJ exome

AF:

0.0513

Gnomad4 EAS exome

AF:

0.0377

Gnomad4 SAS exome

AF:

0.0731

Gnomad4 FIN exome

AF:

0.0370

Gnomad4 NFE exome

AF:

0.0464

Gnomad4 OTH exome

AF:

0.0446

GnomAD4 genome

AF:

0.0132

AC:

1377

AN:

103970

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

618

AN XY:

48524

show subpopulations

Gnomad4 AFR

AF:

0.0302

Gnomad4 AMR

AF:

0.00665

Gnomad4 ASJ

AF:

0.000670

Gnomad4 EAS

AF:

0.00189

Gnomad4 SAS

AF:

0.00605

Gnomad4 FIN

AF:

0.00111

Gnomad4 NFE

AF:

0.00970

Gnomad4 OTH

AF:

0.0159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2016	Variant summary: The TSC1 c.2626-6_2626-4dupTTT variant involves the duplication of three nucleotides in an intronic region. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2772/80186 control chromosomes (50 homozygotes) at a frequency of 0.0345696, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Tuberous sclerosis 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2024	- -

Tuberous sclerosis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Isolated focal cortical dysplasia type II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over