rs739442

chr9-132894747-G-Achr9-132894747-G-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.*1488C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 217,942 control chromosomes in the GnomAD database, including 28,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (18187 hom., cov: 29)
  • Exomes 𝑓: 0.52 (9954 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.581

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=-0.84).
• BP6: Variant 9-132894747-G-A is Benign according to our data. Variant chr9-132894747-G-A is described in ClinVar as [Benign]. Clinvar id is 365477.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132894747-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.*1488C>T		3_prime_UTR_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.*1488C>T		3_prime_UTR_variant	23/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67595 AN: 150714 Hom.: 18192 Cov.: 29

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.524 AC: 35222 AN: 67156 Hom.: 9954 Cov.: 0 AF XY: 0.531 AC XY: 16497 AN XY: 31080

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.433

Gnomad4 ASJ exome AF: 0.606

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.584

Gnomad4 FIN exome AF: 0.521

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.499

GnomAD4 genome AF: 0.448 AC: 67590 AN: 150786 Hom.: 18187 Cov.: 29 AF XY: 0.455 AC XY: 33455 AN XY: 73518

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.490

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.575

Gnomad4 SAS AF: 0.641

Gnomad4 FIN AF: 0.615

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.466

Alfa AF: 0.527 Hom.: 17048

Bravo AF: 0.418

Asia WGS AF: 0.581 AC: 2015 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 13, 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 13, 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	-0.84
Cadd	Benign	0.30
Dann	Benign	0.67

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: rs739442; hg19: chr9-135770134; COSMIC: COSV53765006; COSMIC: COSV53765006;