9-132897613-GAA-G

Position:

chr9-132897613-GAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000298552.9(TSC1):c.2626-5_2626-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,329,542 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.000086 ( 1 hom., cov: 0)

Exomes 𝑓: 0.014 ( 0 hom. )

Consequence

TSC1
ENST00000298552.9 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.485

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 -16 ACMG points.

BP6

Variant 9-132897613-GAA-G is Benign according to our data. Variant chr9-132897613-GAA-G is described in ClinVar as [Benign]. Clinvar id is 195564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132897613-GAA-G is described in Lovd as [Benign]. Variant chr9-132897613-GAA-G is described in Lovd as [Benign]. Variant chr9-132897613-GAA-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0138 (16875/1225416) while in subpopulation AFR AF= 0.0273 (735/26964). AF 95% confidence interval is 0.0256. There are 0 homozygotes in gnomad4_exome. There are 8574 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.2626-5_2626-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 linkuse as main transcript	c.2626-5_2626-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000368.5	ENSP00000298552	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.0000672

AC:

AN:

104126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000101

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:

0.0000918

Gnomad OTH

AF:

0.000728

GnomAD3 exomes

AF:

0.0473

AC:

4915

AN:

103824

Hom.:

AF XY:

0.0473

AC XY:

2713

AN XY:

57384

show subpopulations

Gnomad AFR exome

AF:

0.0679

Gnomad AMR exome

AF:

0.0322

Gnomad ASJ exome

AF:

0.0375

Gnomad EAS exome

AF:

0.0400

Gnomad SAS exome

AF:

0.0317

Gnomad FIN exome

AF:

0.0465

Gnomad NFE exome

AF:

0.0535

Gnomad OTH exome

AF:

0.0384

GnomAD4 exome

AF:

0.0138

AC:

16875

AN:

1225416

Hom.:

AF XY:

0.0141

AC XY:

8574

AN XY:

608580

show subpopulations

Gnomad4 AFR exome

AF:

0.0273

Gnomad4 AMR exome

AF:

0.0235

Gnomad4 ASJ exome

AF:

0.0210

Gnomad4 EAS exome

AF:

0.0211

Gnomad4 SAS exome

AF:

0.0124

Gnomad4 FIN exome

AF:

0.0252

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.0164

GnomAD4 genome

AF:

0.0000864

AC:

AN:

104126

Hom.:

Cov.:

AF XY:

0.0000617

AC XY:

AN XY:

48592

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000101

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000918

Gnomad4 OTH

AF:

0.00216

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Tuberous sclerosis 1

Benign:2

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	Feb 04, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2020	This alteration is classified as 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. -

Tuberous sclerosis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Lymphangiomyomatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 30, 2023

Population allele frequency is 4.7% (rs118203716, 4,915/103,824 alleles in gnomAD v2.1). Based on classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria are met: BA1. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 28, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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