9-132925616-G-C

Position:

• chr9-132925616-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001362177.2(TSC1):​c.-30C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_001362177.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.14

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]

TSC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.334C>G	p.Leu112Val	missense_variant	5/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.334C>G	p.Leu112Val	missense_variant	5/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.334C>G	p.Leu112Val	missense_variant	6/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T;T;.;.;.;T;T;.;.;T;T;T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.7	L;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.033	D;D;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Benign	0.18	T;T;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Polyphen		0.96	D;D;.;D;.;D;.;.;B;B;B;.;.;B;.;.
Vest4		0.49
MutPred		0.91		Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);Loss of glycosylation at P114 (P = 0.1191);
MVP		0.79
MPC		0.63
ClinPred		0.67	D
GERP RS		4.4
Varity_R		0.18
gMVP		0.45

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: chr9-135801003;