rs118203699

chr9-132901606-T-Achr9-132901606-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000368.5(TSC1):c.2485A>T(p.Ser829Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S829R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.36

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TSC1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2485A>T	p.Ser829Cys	missense_variant	19/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2485A>T	p.Ser829Cys	missense_variant	19/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;D;.;D;.;D;.;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.7	L;.;L;.;L;.;L;.;.;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N;D;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.0080	D;D;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;D;.;.;.
Vest4		0.63
MutPred		0.22		Loss of disorder (P = 0.0151);.;Loss of disorder (P = 0.0151);.;Loss of disorder (P = 0.0151);.;Loss of disorder (P = 0.0151);.;.;.;
MVP		0.72
MPC		1.3
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs118203699; hg19: chr9-135776993;