9-132896398-C-G

Variant names:

• chr9-132896398-C-G
• NM_000368.5:c.3332G>C

Variant summary

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

The NM_000368.5(TSC1):​c.3332G>C​(p.Ser1111Thr) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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=0.085993886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.3332G>C	p.Ser1111Thr	missense_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.3332G>C	p.Ser1111Thr	missense_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.3332G>C	p.Ser1111Thr	missense_variant	Exon 24 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	0.079
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.67
DEOGEN2	Benign	0.34	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.42	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.39	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.69	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.93	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.049	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.079
MutPred		0.13		Loss of phosphorylation at S1111 (P = 0.0298);.;Loss of phosphorylation at S1111 (P = 0.0298);.;.;Loss of phosphorylation at S1111 (P = 0.0298);.;Loss of phosphorylation at S1111 (P = 0.0298);.;.;.;
MVP		0.62
MPC		0.46
ClinPred		0.16	T
GERP RS		3.5
Varity_R		0.036
gMVP		0.13

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: chr9-135771785;