9-132897612-T-TAAA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000368.5(TSC1):c.2626-3_2626-2insTTT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 14)
  • Exomes 𝑓: 0.00049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.387

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2626-3_2626-2insTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-3_2626-2insTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5 AN: 43656 Hom.: 0 Cov.: 14 FAILED QC

Gnomad AFR AF: 0.000112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000115

Gnomad OTH AF: 0.00185

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000493 AC: 427 AN: 866556 Hom.: 0 Cov.: 27 AF XY: 0.000555 AC XY: 242 AN XY: 436108

Gnomad4 AFR exome AF: 0.000213

Gnomad4 AMR exome AF: 0.000803

Gnomad4 ASJ exome AF: 0.000589

Gnomad4 EAS exome AF: 0.000674

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.000633

Gnomad4 NFE exome AF: 0.000357

Gnomad4 OTH exome AF: 0.000618

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000115 AC: 5 AN: 43656 Hom.: 0 Cov.: 14 AF XY: 0.000148 AC XY: 3 AN XY: 20336

Gnomad4 AFR AF: 0.000112

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000115

Gnomad4 OTH AF: 0.00185

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 852556). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 20 of the TSC1 gene. It does not directly change the encoded amino acid sequence of the TSC1 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs760737807; hg19: chr9-135772999;