9-132927168-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000368.5(TSC1):c.210+33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00901 in 1,602,738 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0092 ( 106 hom. )

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -1.30

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=-0.89).

BP6

Variant 9-132927168-C-T is Benign according to our data. Variant chr9-132927168-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132927168-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00742 (1130/152318) while in subpopulation SAS AF= 0.0199 (96/4832). AF 95% confidence interval is 0.0167. There are 12 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.210+33G>A		intron_variant	Intron 4 of 22	ENST00000298552.9	NP_000359.1	Q92574-1Q86WV8X5D9D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 link	c.210+33G>A		intron_variant	Intron 4 of 22	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.210+33G>A		intron_variant	Intron 5 of 23	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

AF:

0.00742

AC:

1130

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00945

AC:

2317

AN:

245130

Hom.:

AF XY:

0.0103

AC XY:

1367

AN XY:

132124

show subpopulations

Gnomad AFR exome

AF:

0.00127

Gnomad AMR exome

AF:

0.00796

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.00489

Gnomad SAS exome

AF:

0.0198

Gnomad FIN exome

AF:

0.00165

Gnomad NFE exome

AF:

0.00920

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00918

AC:

13315

AN:

1450420

Hom.:

106

Cov.:

AF XY:

0.00960

AC XY:

6929

AN XY:

721426

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00824

Gnomad4 ASJ exome

AF:

0.0237

Gnomad4 EAS exome

AF:

0.00162

Gnomad4 SAS exome

AF:

0.0201

Gnomad4 FIN exome

AF:

0.00254

Gnomad4 NFE exome

AF:

0.00881

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00742

AC:

1130

AN:

152318

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00798

Gnomad4 ASJ

AF:

0.0323

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Tuberous sclerosis 1

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome

Other:1

Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.048

DANN

Benign

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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