rs10491534

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000368.5(TSC1):c.*1934A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 231,140 control chromosomes in the GnomAD database, including 2,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.14 ( 1724 hom., cov: 32)

Exomes 𝑓: 0.10 ( 462 hom. )

Consequence

TSC1
NM_000368.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.172

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 9-132894301-T-C is Benign according to our data. Variant chr9-132894301-T-C is described in ClinVar as [Benign]. Clinvar id is 365466.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.*1934A>G		3_prime_UTR_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9 linkuse as main transcript	c.*1934A>G		3_prime_UTR_variant	23/23	1	NM_000368.5	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21063

AN:

152076

Hom.:

1724

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0814

Gnomad ASJ

AF:

0.0957

Gnomad EAS

AF:

0.0657

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0922

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.131

GnomAD4 exome

AF:

0.100

AC:

7906

AN:

78946

Hom.:

462

Cov.:

AF XY:

0.0991

AC XY:

3608

AN XY:

36390

show subpopulations

Gnomad4 AFR exome

AF:

0.238

Gnomad4 AMR exome

AF:

0.0867

Gnomad4 ASJ exome

AF:

0.0949

Gnomad4 EAS exome

AF:

0.0346

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.0990

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.139

AC:

21081

AN:

152194

Hom.:

1724

Cov.:

AF XY:

0.135

AC XY:

10054

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.239

Gnomad4 AMR

AF:

0.0813

Gnomad4 ASJ

AF:

0.0957

Gnomad4 EAS

AF:

0.0655

Gnomad4 SAS

AF:

0.102

Gnomad4 FIN

AF:

0.0922

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.111

Hom.:

1464

Bravo

AF:

0.141

Asia WGS

AF:

0.113

AC:

393

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

Cadd

Benign

3.6

Dann

Benign

0.82

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