chr9-132923378-G-A

Position:

chr9-132923378-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000368.5(TSC1):c.478C>T(p.Arg160Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.33

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000368.5

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.478C>T	p.Arg160Cys	missense_variant	6/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9 linkuse as main transcript	c.478C>T	p.Arg160Cys	missense_variant	6/23	1	NM_000368.5	P4	Q92574-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 13, 2021

- -

Tuberous sclerosis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 17, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function. ClinVar contains an entry for this variant (Variation ID: 466144). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the TSC1 protein (p.Arg160Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2022

The p.R160C variant (also known as c.478C>T), located in coding exon 4 of the TSC1 gene, results from a C to T substitution at nucleotide position 478. The arginine at codon 160 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.5

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.1

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.79

Gain of catalytic residue at L161 (P = 0.0274);.;Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);.;.;Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);Gain of catalytic residue at L161 (P = 0.0274);.;Gain of catalytic residue at L161 (P = 0.0274);.;Gain of catalytic residue at L161 (P = 0.0274);

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.85

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