rs118203466

Positions:

• chr9-132912283-A-C
• chr9-132912283-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_000368.5(TSC1):​c.912T>G​(p.Tyr304Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y304Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9829
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 9-132912283-A-C is Pathogenic according to our data. Variant chr9-132912283-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49122.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132912283-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.912T>G	p.Tyr304Ter	stop_gained, splice_region_variant	9/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.912T>G	p.Tyr304Ter	stop_gained, splice_region_variant	9/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences

Jul 14, 2022

The stop gained NM_000368.5(TSC1):c.912T>G (p.Tyr304Ter) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr304Ter variant is novel (not in any individuals) in 1kG All. The p.Tyr304Ter variant is novel (not in any individuals) in gnomAD as well as in our inhouse database. The variant was previously reported in ClinVar database with no assertion criteria (Accession: VCV000049122.2). This variant is predicted to cause loss of normal protein function through protein truncation. This variant is a stop gained variant which occurs in an exon of TSC1 upstream of where nonsense mediated decay is predicted to occur. There are 282 downstream pathogenic loss of function variants, with the furthest variant being 652 residues downstream of this variant. This indicates that the region is critical to protein function. The gene TSC1 has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.12. The p.Tyr304Ter variant is a loss of function variant in the gene TSC1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000359.1:p.Q4* and 343 others. For these reasons, this variant has been classified as Likely Pathogenic. -

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
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;D
Vest4		0.89
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203466; hg19: chr9-135787670;