9-132907331-G-C

Variant names:

• chr9-132907331-G-C
• NM_000368.5:c.1303C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000368.5(TSC1):​c.1303C>G​(p.Gln435Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22152236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1303C>G	p.Gln435Glu	missense_variant	Exon 13 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1303C>G	p.Gln435Glu	missense_variant	Exon 13 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1303C>G	p.Gln435Glu	missense_variant	Exon 14 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Sep 09, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q435E variant (also known as c.1303C>G), located in coding exon 11 of the TSC1 gene, results from a C to G substitution at nucleotide position 1303. The glutamine at codon 435 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.42	T;.;T;.;.;T;.;T;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	.;T;T;T;T;.;.;.;T;T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.7	L;.;L;.;.;L;.;L;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.62	N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.018	D;D;D;.;.;.;.;.;.;.;.;.
Polyphen		0.070	B;.;B;.;.;B;.;B;.;.;.;.
Vest4		0.36
MutPred		0.45		Gain of relative solvent accessibility (P = 0.0289);.;Gain of relative solvent accessibility (P = 0.0289);.;.;Gain of relative solvent accessibility (P = 0.0289);.;Gain of relative solvent accessibility (P = 0.0289);.;Gain of relative solvent accessibility (P = 0.0289);.;.;
MVP		0.71
MPC		0.56
ClinPred		0.66	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135782718;