9-132911475-C-G

Variant names:

• chr9-132911475-C-G
• rs397514808
• NM_000368.5:c.1007G>C

Variant summary

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

The NM_000368.5(TSC1):​c.1007G>C​(p.Arg336Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, 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 2 ACMG points.

• 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.1007G>C	p.Arg336Pro	missense	Exon 10 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.1007G>C	p.Arg336Pro	missense	Exon 10 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.1007G>C	p.Arg336Pro	missense	Exon 10 of 23	NP_001393522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1007G>C	p.Arg336Pro	missense	Exon 10 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.1007G>C	p.Arg336Pro	missense	Exon 11 of 24	ENSP00000495533.2
	TSC1	ENST00000403810.6	TSL:1	c.1007G>C	p.Arg336Pro	missense	Exon 10 of 10	ENSP00000386093.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.00099
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.57
Sift	Benign	0.049	D
Sift4G	Benign	0.085	T
Polyphen		0.0	B
Vest4		0.64
MutPred		0.58		Gain of glycosylation at R336 (P = 0.0238)
MVP		0.95
MPC		1.5
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.38
Mutation Taster		=79/21	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: rs397514808; hg19: chr9-135786862;