9-132891798-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000368.5(TSC1):c.*4437G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 233,568 control chromosomes in the GnomAD database, including 1,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1450 hom., cov: 33)
  • Exomes 𝑓: 0.084 (315 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.820

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-132891798-C-T is Benign according to our data. Variant chr9-132891798-C-T is described in ClinVar as [Benign]. Clinvar id is 365392.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132891798-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.*4437G>A		3_prime_UTR_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.*4437G>A		3_prime_UTR_variant	23/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17495 AN: 152100 Hom.: 1443 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0714

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.0836 AC: 6799 AN: 81350 Hom.: 315 Cov.: 0 AF XY: 0.0816 AC XY: 3055 AN XY: 37450

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0541

Gnomad4 EAS exome AF: 0.0652

Gnomad4 SAS exome AF: 0.0456

Gnomad4 FIN exome AF: 0.0519

Gnomad4 NFE exome AF: 0.0757

Gnomad4 OTH exome AF: 0.0988

GnomAD4 genome AF: 0.115 AC: 17538 AN: 152218 Hom.: 1450 Cov.: 33 AF XY: 0.113 AC XY: 8421 AN XY: 74422

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0616

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.0510

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.0714

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0882 Hom.: 710

Bravo AF: 0.130

Asia WGS AF: 0.0690 AC: 241 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Tuberous sclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	14
Dann	Benign	0.81

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: rs11553763; hg19: chr9-135767185;