rs118203662

Variant names:

• chr9-132902747-C-A
• rs118203662
• NM_000368.5:c.2249G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132902747-C-A
• chr9-132902747-C-T
• chr9-132902747-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000368.5(TSC1):​c.2249G>T​(p.Trp750Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106069505).

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.2249G>T	p.Trp750Leu	missense	Exon 18 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2249G>T	p.Trp750Leu	missense	Exon 18 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2249G>T	p.Trp750Leu	missense	Exon 18 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.2249G>T	p.Trp750Leu	missense	Exon 18 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2249G>T	p.Trp750Leu	missense	Exon 19 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2249G>T	p.Trp750Leu	missense	Exon 18 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.0060
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.1	N
PhyloP100		5.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	2.9	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.40
MutPred		0.40		Gain of disorder (P = 0.0342)
MVP		0.13
MPC		0.89
ClinPred		0.86	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.33
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs118203662; hg19: chr9-135778134;