rs753388676

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_000368.5(TSC1):c.3194C>T(p.Thr1065Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1065T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 3.84

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 -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.103717).

BP6

Variant 9-132896536-G-A is Benign according to our data. Variant chr9-132896536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 207642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.3194C>T	p.Thr1065Met	missense_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.3194C>T	p.Thr1065Met	missense_variant	23/23	1	NM_000368.5	ENSP00000298552	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251372

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

TSC1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The TSC1 c.3194C>T variant is predicted to result in the amino acid substitution p.Thr1065Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted in ClinVar as benign and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/207642/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2021

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.33

T;.;T;.;.;T;.;T;.;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.69

.;T;T;T;T;.;.;.;T;T;.

M_CAP

Benign

0.064

MetaRNN

Benign

0.10

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.1

M;.;M;.;.;M;.;M;.;.;.

MutationTaster

Benign

0.99

D;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.45

N;N;N;.;.;.;.;.;.;.;.

REVEL

Benign

0.24

Sift

Uncertain

0.023

D;D;D;.;.;.;.;.;.;.;.

Sift4G

Benign

0.10

T;T;T;.;.;.;.;.;.;.;.

Polyphen

0.80

P;.;P;.;.;P;.;P;.;.;.

Vest4

0.16

MutPred

0.12

Loss of phosphorylation at T1065 (P = 0.0497);.;Loss of phosphorylation at T1065 (P = 0.0497);.;.;Loss of phosphorylation at T1065 (P = 0.0497);.;Loss of phosphorylation at T1065 (P = 0.0497);.;.;.;

MVP

0.47

MPC

0.88

ClinPred

0.059

GERP RS

2.5

Varity_R

0.015

gMVP

0.18

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