9-132901734-A-G

Position:

• chr9-132901734-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000298552.9(TSC1):​c.2392-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,602,802 control chromosomes in the GnomAD database, including 20,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3489 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16515 hom.)
• Consequence: TSC1 ENST00000298552.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.131

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-132901734-A-G is Benign according to our data. Variant chr9-132901734-A-G is described in ClinVar as [Benign]. Clinvar id is 48948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132901734-A-G is described in Lovd as [Benign]. Variant chr9-132901734-A-G is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2392-35T>C		intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2392-35T>C		intron_variant		1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29414 AN: 151994 Hom.: 3474 Cov.: 32

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0848

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.172

GnomAD3 exomes AF: 0.142 AC: 35526 AN: 249528 Hom.: 3002 AF XY: 0.138 AC XY: 18613 AN XY: 134968

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.0945

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0875

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.145 AC: 210897 AN: 1450690 Hom.: 16515 Cov.: 27 AF XY: 0.143 AC XY: 103494 AN XY: 722396

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.0984

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.0711

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.194 AC: 29462 AN: 152112 Hom.: 3489 Cov.: 32 AF XY: 0.187 AC XY: 13907 AN XY: 74372

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0850

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.176

Alfa AF: 0.170 Hom.: 573

Bravo AF: 0.200

Asia WGS AF: 0.135 AC: 473 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with tuberous sclerosis -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	This variant is associated with the following publications: (PMID: 27884173, 10533066, 17304050) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tuberous sclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.8
DANN	Benign	0.28

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

Other links and lift over

dbSNP: rs11243931; hg19: chr9-135777121; COSMIC: COSV53763230;