chr9-132911535-C-A

Variant names:

• chr9-132911535-C-A
• rs375956049
• NM_000368.5:c.947G>T

Variant summary

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

The NM_001406626.1(TSC1):​c.-5G>T variant causes a 5 prime UTR premature start codon gain 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: TSC1 NM_001406626.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.32
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406626.1. 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.947G>T	p.Arg316Leu	missense	Exon 10 of 23	NP_000359.1
	TSC1	NM_001406626.1		c.-5G>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 22	NP_001393555.1
	TSC1	NM_001406627.1		c.-5G>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 22	NP_001393556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.947G>T	p.Arg316Leu	missense	Exon 10 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.947G>T	p.Arg316Leu	missense	Exon 11 of 24	ENSP00000495533.2
	TSC1	ENST00000403810.6	TSL:1	c.947G>T	p.Arg316Leu	missense	Exon 10 of 10	ENSP00000386093.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.59
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.061	B
Vest4		0.66
MutPred		0.62		Loss of phosphorylation at T314 (P = 0.0707)
MVP		0.93
MPC		0.67
ClinPred		0.74	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.53
Mutation Taster		=74/26	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: rs375956049; hg19: chr9-135786922;