9-132905635-A-G

Position:

chr9-132905635-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

The NM_000368.5(TSC1):c.1943T>C(p.Val648Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,082 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 9.10

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_benign. Variant got -3 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.749

BP6

Variant 9-132905635-A-G is Benign according to our data. Variant chr9-132905635-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207612.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5 linkuse as main transcript	c.1943T>C	p.Val648Ala	missense_variant	15/23	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.1943T>C	p.Val648Ala	missense_variant	15/23	1	NM_000368.5	ENSP00000298552	P4	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.00000796

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727248

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:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

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:

0.0000936

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The p.V648A variant (also known as c.1943T>C), located in coding exon 13 of the TSC1 gene, results from a T to C substitution at nucleotide position 1943. The valine at codon 648 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.50

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

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

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

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

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.75

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

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.5

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

D;N;D;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.99

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

Vest4

0.85

MutPred

0.74

Gain of disorder (P = 0.0425);.;Gain of disorder (P = 0.0425);.;.;Gain of disorder (P = 0.0425);.;Gain of disorder (P = 0.0425);.;Gain of disorder (P = 0.0425);.;

MVP

0.66

MPC

0.87

ClinPred

0.81

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.50

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