rs1554813029

Variant names:

• chr9-132896744-A-C
• rs1554813029
• NM_000368.5:c.2986T>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000368.5(TSC1):​c.2986T>G​(p.Cys996Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.56

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.072053015).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2986T>G	p.Cys996Gly	missense_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2986T>G	p.Cys996Gly	missense_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2986T>G	p.Cys996Gly	missense_variant	Exon 24 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461412 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated focal cortical dysplasia type II Uncertain:1

Jun 04, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 1 Uncertain:1

Sep 09, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function. ClinVar contains an entry for this variant (Variation ID: 466109). 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 cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 996 of the TSC1 protein (p.Cys996Gly). -

Hereditary cancer-predisposing syndrome Benign:1

Jul 03, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.31	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.;M;.;M;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.28	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.71	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.48	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.10
MutPred		0.29		Loss of stability (P = 0.0047);.;Loss of stability (P = 0.0047);.;.;Loss of stability (P = 0.0047);.;Loss of stability (P = 0.0047);.;.;.;
MVP		0.24
MPC		0.62
ClinPred		0.14	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs1554813029; hg19: chr9-135772131;