NM_000368.5:c.245A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 29 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.245A>C	p.Lys82Thr	missense	Exon 5 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.245A>C	p.Lys82Thr	missense	Exon 5 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.245A>C	p.Lys82Thr	missense	Exon 5 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.245A>C	p.Lys82Thr	missense	Exon 5 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.245A>C	p.Lys82Thr	missense	Exon 6 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000403810.6	TSL:1	c.245A>C	p.Lys82Thr	missense	Exon 5 of 10	ENSP00000386093.1	Q86WV8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.25	B
Vest4		0.57
MutPred		0.65		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
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs118203356; hg19: chr9-135801092;