Genetic Variant TSC1:p.Gln413Pro (chr9-132910596-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000368.5(TSC1):c.1238A>C(p.Gln413Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. Q413R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.47

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
lung lymphangioleiomyomatosis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
tuberous sclerosis complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1125913).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC1	NM_000368.5	MANE Select	c.1238A>C	p.Gln413Pro	missense	Exon 12 of 23	NP_000359.1	Q92574-1
TSC1	NM_001406592.1		c.1238A>C	p.Gln413Pro	missense	Exon 12 of 23	NP_001393521.1	X5D9D2
TSC1	NM_001406593.1		c.1238A>C	p.Gln413Pro	missense	Exon 12 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1238A>C	p.Gln413Pro	missense	Exon 12 of 23	ENSP00000298552.3	Q92574-1
TSC1	ENST00000490179.4	TSL:3	c.1238A>C	p.Gln413Pro	missense	Exon 13 of 24	ENSP00000495533.2	Q92574-1
TSC1	ENST00000493467.6	TSL:1	n.509A>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.0045

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.74

M_CAP

Benign

0.044

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.91

PhyloP100

1.5

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.48

REVEL

Benign

0.17

Sift

Benign

0.088

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.26

MutPred

0.45

Gain of catalytic residue at P412 (P = 0.0107)

MVP

0.51

MPC

0.61

ClinPred

0.069

GERP RS

2.0

Varity_R

0.058

gMVP

0.37

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over