9-132911452-C-T

Position:

• chr9-132911452-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000368.5(TSC1):​c.1029+1G>A variant causes a splice donor change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.64

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-132911452-C-T is Pathogenic according to our data. Variant chr9-132911452-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132911452-C-T is described in Lovd as [Pathogenic]. Variant chr9-132911452-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1029+1G>A		splice_donor_variant		ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1029+1G>A		splice_donor_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251294 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change affects a donor splice site in intron 10 of the TSC1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs118203485, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with tuberous sclerosis complex (PMID: 10533069; Invitae). ClinVar contains an entry for this variant (Variation ID: 48729). Studies have shown that disruption of this splice site results in inclusion of intron 10 and introduces a premature termination codon (PMID: 10533069). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.1029+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the TSC1 gene. This alteration was identified in 1 of 243 unrelated Chinese probands with a clinical diagnosis of TSC (Ding Y et al. Front Genet, 2020 Mar;11:204). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is 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	0.30	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MutationTaster	Benign	1.0	D;D;D;D;N
ClinPred		0.62	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		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: rs118203485; hg19: chr9-135786839;