Variant rs739442 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.581

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 -20 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.*1488C>T		3_prime_UTR_variant	23/23	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.*1488C>T		3_prime_UTR_variant	23/23	1	NM_000368.5	ENSP00000298552	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

67595

AN:

150714

Hom.:

18192

Cov.:

show subpopulations

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.:

AF XY:

0.531

AC XY:

16497

AN XY:

31080

show subpopulations

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.:

AF XY:

0.455

AC XY:

33455

AN XY:

73518

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

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