9-132911506-G-C

Variant names:

• chr9-132911506-G-C
• NM_000368.5:c.976C>G

Variant summary

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

The NM_000368.5(TSC1):​c.976C>G​(p.Leu326Val) 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17

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.976C>G	p.Leu326Val	missense_variant	Exon 10 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.976C>G	p.Leu326Val	missense_variant	Exon 10 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.976C>G	p.Leu326Val	missense_variant	Exon 11 of 24	3		ENSP00000495533.2

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	Benign	0.080
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T;T;T;.;.;.;T;T;.;D;.;.;T;D;T;T;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.34	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.39	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
Sift4G	Benign	0.17	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.15	B;.;B;.;B;.;B;.;.;.;.;P;P;P;.;.;.;P
Vest4		0.44
MutPred		0.72		Gain of phosphorylation at T329 (P = 0.1116);.;Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);.;.;Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);Gain of phosphorylation at T329 (P = 0.1116);.;Gain of phosphorylation at T329 (P = 0.1116);
MVP		0.70
MPC		0.98
ClinPred		0.73	D
GERP RS		5.8
Varity_R		0.078
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr9-135786893;