9-132925588-T-C

Position:

• chr9-132925588-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 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. K121N) has been classified as Likely pathogenic.

• 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

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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 Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.362A>G	p.Lys121Arg	missense_variant, splice_region_variant	5/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.362A>G	p.Lys121Arg	missense_variant, splice_region_variant	5/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.362A>G	p.Lys121Arg	missense_variant, splice_region_variant	6/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

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;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.5	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.020	D;D;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Uncertain	0.016	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.93	P;P;.;P;.;P;.;.;D;D;D;.;.;D;.;.
Vest4		0.89
MutPred		0.82		Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);Loss of ubiquitination at K121 (P = 0.0224);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203369; hg19: chr9-135800975;