9-132891798-C-T

Variant summary

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

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

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.820
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]

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=-0.54).
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_multiple_submitters_no_conflicts, 2 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 Protein UniProt
TSC1NM_000368.5 linkuse as main transcriptc.*4437G>A 3_prime_UTR_variant 23/23 ENST00000298552.9 NP_000359.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC1ENST00000298552.9 linkuse as main transcriptc.*4437G>A 3_prime_UTR_variant 23/231 NM_000368.5 ENSP00000298552 P4Q92574-1

Frequencies

GnomAD3 genomes
AF:
0.115
AC:
17495
AN:
152100
Hom.:
1443
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Isolated focal cortical dysplasia type II Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11553763; hg19: chr9-135767185; API