rs118203493

chr9-132911064-G-Achr9-132911064-G-Cchr9-132911064-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000368.5(TSC1):c.1079C>T(p.Thr360Ile) variant causes a missense change. 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. T360P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TSC1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1079C>T	p.Thr360Ile	missense_variant	11/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1079C>T	p.Thr360Ile	missense_variant	11/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.3	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.2	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.53
Sift	Benign	0.043	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.023	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.98	D;.;D;.;D;.;D;.;.;.;D;D;D;.;.
Vest4		0.68
MutPred		0.48		Loss of glycosylation at T360 (P = 0.0032);.;Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);.;Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);Loss of glycosylation at T360 (P = 0.0032);.;
MVP		0.64
MPC		1.4
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs118203493; hg19: chr9-135786451;