chr9-132911457-G-C

Variant names:

• chr9-132911457-G-C
• rs1060503197
• NM_000368.5:c.1025C>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.1025C>G​(p.Pro342Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. P342S) 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: 2.91
• 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, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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=0.21307236).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.1025C>G	p.Pro342Arg	missense	Exon 10 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.1025C>G	p.Pro342Arg	missense	Exon 10 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.1025C>G	p.Pro342Arg	missense	Exon 10 of 23	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1025C>G	p.Pro342Arg	missense	Exon 10 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.1025C>G	p.Pro342Arg	missense	Exon 11 of 24	ENSP00000495533.2
	TSC1	ENST00000403810.6	TSL:1	c.1025C>G	p.Pro342Arg	missense	Exon 10 of 10	ENSP00000386093.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.53
Sift	Benign	0.52	T
Sift4G	Benign	0.56	T
Polyphen		0.12	B
Vest4		0.43
MutPred		0.59		Loss of catalytic residue at P341 (P = 0.0096)
MVP		0.95
MPC		0.56
ClinPred		0.12	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.17
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1060503197; hg19: chr9-135786844;