9-132911481-G-C

Variant names:

• chr9-132911481-G-C
• NM_000368.5:c.1001C>G

Variant summary

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

The NM_001406629.1(TSC1):​c.-93C>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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_001406629.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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.1001C>G	p.Ser334Trp	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.1001C>G	p.Ser334Trp	missense_variant	Exon 10 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1001C>G	p.Ser334Trp	missense_variant	Exon 11 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1380007). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the TSC1 protein (p.Ser334Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.012	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
Polyphen		0.99	D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D
Vest4		0.59
MutPred		0.61		Loss of glycosylation at S334 (P = 0.0323);.;Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);.;.;Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);Loss of glycosylation at S334 (P = 0.0323);.;Loss of glycosylation at S334 (P = 0.0323);
MVP		0.88
MPC		1.5
ClinPred		0.89	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr9-135786868;