rs118203519

Variant names:

• chr9-132906815-C-A
• NM_000368.5:c.1354G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132906815-C-A
• chr9-132906815-C-G
• chr9-132906815-C-T

Variant summary

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

The NM_000368.5(TSC1):​c.1354G>T​(p.Gly452Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G452R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1354G>T	p.Gly452Cys	missense_variant	Exon 14 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1354G>T	p.Gly452Cys	missense_variant	Exon 14 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1354G>T	p.Gly452Cys	missense_variant	Exon 15 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T;.;.;T;.;T;.;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;.;.;.;D;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.;M;.;M;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.70	N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.015	D;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.058	T;T;T;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.;.
Vest4		0.45
MutPred		0.66		Gain of methylation at K451 (P = 0.0293);.;Gain of methylation at K451 (P = 0.0293);.;.;Gain of methylation at K451 (P = 0.0293);.;Gain of methylation at K451 (P = 0.0293);.;Gain of methylation at K451 (P = 0.0293);.;.;
MVP		0.64
MPC		1.4
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr9-135782202;