9-132896610-G-T

Position:

• chr9-132896610-G-T

Variant summary

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

The NM_000368.5(TSC1):​c.3120C>A​(p.Ser1040Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05

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=0.24688628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.3120C>A	p.Ser1040Arg	missense_variant	23/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.3120C>A	p.Ser1040Arg	missense_variant	23/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.3120C>A	p.Ser1040Arg	missense_variant	24/24	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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;T;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.;M;.;M;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.070	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.022	D;D;D;.;.;.;.;.;.;.;.
Polyphen		0.61	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.20
MutPred		0.36		Loss of phosphorylation at S1040 (P = 7e-04);.;Loss of phosphorylation at S1040 (P = 7e-04);.;.;Loss of phosphorylation at S1040 (P = 7e-04);.;Loss of phosphorylation at S1040 (P = 7e-04);.;.;.;
MVP		0.62
MPC		0.74
ClinPred		0.58	D
GERP RS		5.4
Varity_R		0.064
gMVP		0.31

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: chr9-135771997;