9-132925705-T-G

Variant names:

• chr9-132925705-T-G
• rs118203356
• NM_000368.5:c.245A>C

Variant summary

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

The NM_000368.5(TSC1):​c.245A>C​(p.Lys82Thr) variant causes a missense 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.30

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.245A>C	p.Lys82Thr	missense_variant	Exon 5 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.245A>C	p.Lys82Thr	missense_variant	Exon 5 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.245A>C	p.Lys82Thr	missense_variant	Exon 6 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Malignant tumor of urinary bladder Other:1

-

Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.4	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0080	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.25	B;B;.;B;.;B;.;.;P;P;P;.;.;P;.;.
Vest4		0.57
MutPred		0.65		Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);Loss of ubiquitination at K82 (P = 0.0233);
MVP		0.82
MPC		1.5
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.19
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118203356; hg19: chr9-135801092;