rs397514867

chr9-132912329-G-Achr9-132912329-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000368.5(TSC1):c.866C>T(p.Ser289Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S289S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42

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
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.36588115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.866C>T	p.Ser289Leu	missense_variant	9/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.866C>T	p.Ser289Leu	missense_variant	9/23	1	NM_000368.5	P4

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	0.072
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.6	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.060	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Benign	0.087	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Polyphen		0.010	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.
Vest4		0.28
MutPred		0.54		Loss of disorder (P = 0.0061);.;Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);.;.;Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);.;Loss of disorder (P = 0.0061);.;
MVP		0.66
MPC		0.51
ClinPred		0.77	D
GERP RS		4.8
Varity_R		0.082
gMVP		0.28

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: chr9-135787716; COSMIC: COSV53766497; COSMIC: COSV53766497;