9-132911536-G-C

Position:

• chr9-132911536-G-C

Variant summary

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

The NM_001406626.1(TSC1):​c.-6C>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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: TSC1 NM_001406626.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.946C>G	p.Arg316Gly	missense_variant	10/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.946C>G	p.Arg316Gly	missense_variant	10/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.946C>G	p.Arg316Gly	missense_variant	11/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0070	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		0.64	P;.;P;.;P;.;P;.;.;.;.;P;P;P;.;.;.;P;.
Vest4		0.68
MutPred		0.68		Gain of glycosylation at S315 (P = 0.0421);.;Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);.;.;Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);Gain of glycosylation at S315 (P = 0.0421);.;Gain of glycosylation at S315 (P = 0.0421);.;
MVP		0.87
MPC		1.3
ClinPred		0.84	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.50

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: chr9-135786923;