rs118203369

Positions:

• chr9-132925588-T-A
• chr9-132925588-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001362177.2(TSC1):​c.-2A>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_001362177.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 9-132925588-T-A is Pathogenic according to our data. Variant chr9-132925588-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411244.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.362A>T	p.Lys121Met	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>T	p.Lys121Met	missense_variant, splice_region_variant	5/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.362A>T	p.Lys121Met	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 04, 2020

This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with tuberous sclerosis complex (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 411244). This sequence change replaces lysine with methionine at codon 121 of the TSC1 protein (p.Lys121Met). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;.;D;.;D;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.5	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.93
Sift	Benign	0.057	T;T;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.99	D;D;.;D;.;D;.;.;D;D;D;.;.;D;.;.
Vest4		0.89
MutPred		0.79		Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);
MVP		0.84
MPC		1.6
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		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;