9-132897612-T-TTA

Variant summary

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

The NM_000368.5(TSC1):c.2626-3_2626-2insTA variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 871,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 14)
  • Exomes 𝑓: 0.00016 (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:2
• 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_2626-2insTA		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_2626-2insTA		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 12 AN: 43668 Hom.: 0 Cov.: 14 FAILED QC

Gnomad AFR AF: 0.0000562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000594

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000287

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 141 AN: 871106 Hom.: 0 Cov.: 27 AF XY: 0.000164 AC XY: 72 AN XY: 438680

Gnomad4 AFR exome AF: 0.0000850

Gnomad4 AMR exome AF: 0.0000440

Gnomad4 ASJ exome AF: 0.000260

Gnomad4 EAS exome AF: 0.000235

Gnomad4 SAS exome AF: 0.0000955

Gnomad4 FIN exome AF: 0.000314

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.000214

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000275 AC: 12 AN: 43706 Hom.: 0 Cov.: 14 AF XY: 0.000393 AC XY: 8 AN XY: 20370

Gnomad4 AFR AF: 0.0000561

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00255

Gnomad4 SAS AF: 0.00116

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000287

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Isolated focal cortical dysplasia type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;