9-132910639-G-T

Variant names:

• chr9-132910639-G-T
• NM_000368.5:c.1195C>A

Variant summary

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

The NM_000368.5(TSC1):​c.1195C>A​(p.Pro399Thr) 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. 15/21 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: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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=0.25486505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1195C>A	p.Pro399Thr	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.1195C>A	p.Pro399Thr	missense_variant	Exon 12 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1195C>A	p.Pro399Thr	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	0.070
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Uncertain	0.56	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.
Eigen	Benign	-0.076
Eigen_PC	Benign	0.083
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	.;D;D;D;.;.;.;D;D;.;.;.;D;D;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.94	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.36	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.98	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;.;B;.;B;.;.;.;B;B;B;.;.
Vest4		0.38
MutPred		0.40		Gain of phosphorylation at P399 (P = 0.0394);.;Gain of phosphorylation at P399 (P = 0.0394);.;Gain of phosphorylation at P399 (P = 0.0394);.;Gain of phosphorylation at P399 (P = 0.0394);.;Gain of phosphorylation at P399 (P = 0.0394);.;Gain of phosphorylation at P399 (P = 0.0394);Gain of phosphorylation at P399 (P = 0.0394);Gain of phosphorylation at P399 (P = 0.0394);.;.;
MVP		0.64
MPC		0.79
ClinPred		0.34	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr9-135786026;