9-132910686-C-G

Variant names:

• chr9-132910686-C-G
• NM_000368.5:c.1148G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000368.5(TSC1):​c.1148G>C​(p.Gly383Ala) 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. G383F?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132910686-CC-CGAA is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1148G>C	p.Gly383Ala	missense_variant	Exon 12 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1148G>C	p.Gly383Ala	missense_variant	Exon 12 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1148G>C	p.Gly383Ala	missense_variant	Exon 13 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	0.17
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D;.;.;.;D;D;.;.;.;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.7	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.65
Sift	Benign	0.12	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.030	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;D;.;.;.;D;D;D;.;.
Vest4		0.59
MutPred		0.62		Gain of glycosylation at T386 (P = 0.118);.;Gain of glycosylation at T386 (P = 0.118);.;Gain of glycosylation at T386 (P = 0.118);.;Gain of glycosylation at T386 (P = 0.118);.;Gain of glycosylation at T386 (P = 0.118);.;Gain of glycosylation at T386 (P = 0.118);Gain of glycosylation at T386 (P = 0.118);Gain of glycosylation at T386 (P = 0.118);.;.;
MVP		0.62
MPC		0.60
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr9-135786073;