NM_000368.5:c.1462G>C

Variant names:

• chr9-132906116-C-G
• NM_000368.5:c.1462G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000368.5(TSC1):​c.1462G>C​(p.Glu488Gln) 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. 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. E488D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31151634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1462G>C	p.Glu488Gln	missense_variant	Exon 15 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1462G>C	p.Glu488Gln	missense_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1462G>C	p.Glu488Gln	missense_variant	Exon 16 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 23, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T;.;.;T;.;T;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	2.0	M;.;M;.;.;M;.;M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.74	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.024	D;T;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.26	T;T;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.27
MutPred		0.37		Loss of glycosylation at S483 (P = 0.1933);.;Loss of glycosylation at S483 (P = 0.1933);.;.;Loss of glycosylation at S483 (P = 0.1933);.;Loss of glycosylation at S483 (P = 0.1933);.;Loss of glycosylation at S483 (P = 0.1933);.;
MVP		0.85
MPC		1.2
ClinPred		0.71	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr9-135781503;