chr9-132928879-G-A

Position:

• chr9-132928879-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000368.5(TSC1):​c.-7C>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 0.00116 in 1,613,994 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: TSC1 NM_000368.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -1.49

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-132928879-G-A is Benign according to our data. Variant chr9-132928879-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 64782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132928879-G-A is described in Lovd as [Likely_benign]. Variant chr9-132928879-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00104 (158/152338) while in subpopulation AMR AF= 0.00287 (44/15306). AF 95% confidence interval is 0.0022. There are 1 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.-7C>T		5_prime_UTR_variant	3/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.-7C>T		5_prime_UTR_variant	3/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.-7C>T		5_prime_UTR_variant	4/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00126 AC: 316 AN: 251218 Hom.: 2 AF XY: 0.00145 AC XY: 197 AN XY: 135802

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00117 AC: 1713 AN: 1461656 Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 872 AN XY: 727130

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74490

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2018	c.-7C>T in intron 2 of TSC1: This variant is classified as likely benign because a C>T/T>C change at this position does not diverge from the splice consensus se quence and is therefore unlikely to impact splicing. It has been identified in i n 0.1% (216/126578) of European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org; dbSNP rs62621221). ACMG/AMP Criteria a pplied: BP4, BP7, BS1_Supporting. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2022	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TSC1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Tuberous sclerosis 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Jan 22, 2016

- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs62621221; hg19: chr9-135804266; COSMIC: COSV104595819;