9-132925588-T-C

Variant names:

• chr9-132925588-T-C
• rs118203369
• NM_000368.5:c.362A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000368.5(TSC1):​c.362A>G​(p.Lys121Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K121Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_000368.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.76
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132925587-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 958476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.362A>G	p.Lys121Arg	missense splice_region	Exon 5 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.362A>G	p.Lys121Arg	missense splice_region	Exon 5 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.362A>G	p.Lys121Arg	missense splice_region	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.362A>G	p.Lys121Arg	missense splice_region	Exon 5 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.362A>G	p.Lys121Arg	missense splice_region	Exon 6 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000403810.6	TSL:1	c.362A>G	p.Lys121Arg	missense splice_region	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
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.86
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.016	D
Polyphen		0.93	P
Vest4		0.89
MutPred		0.82		Loss of ubiquitination at K121 (P = 0.0224)
MVP		0.85
MPC		1.3
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.33
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs118203369; hg19: chr9-135800975;