rs5901000

Positions:

• chr9-132897613-GAAAAAA-G
• chr9-132897613-GAAAAAA-GA
• chr9-132897613-GAAAAAA-GAA
• chr9-132897613-GAAAAAA-GAAA
• chr9-132897613-GAAAAAA-GAAAA
• chr9-132897613-GAAAAAA-GAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAAAAAAA
• chr9-132897613-GAAAAAA-GAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The ENST00000298552.9(TSC1):​c.2626-9_2626-4del 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 0.0000538 in 1,358,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: TSC1 ENST00000298552.9 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.18

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-132897613-GAAAAAA-G is Benign according to our data. Variant chr9-132897613-GAAAAAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 3051573.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-9_2626-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-9_2626-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.0000288 AC: 3 AN: 104138 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000415

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: 0.0000367

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000558 AC: 70 AN: 1253942 Hom.: 0 AF XY: 0.0000465 AC XY: 29 AN XY: 623242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000367

Gnomad4 ASJ exome AF: 0.0000990

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000152

Gnomad4 FIN exome AF: 0.0000302

Gnomad4 NFE exome AF: 0.0000628

Gnomad4 OTH exome AF: 0.0000580

GnomAD4 genome AF: 0.0000288 AC: 3 AN: 104138 Hom.: 0 Cov.: 0 AF XY: 0.0000412 AC XY: 2 AN XY: 48580

Gnomad4 AFR AF: 0.0000415

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: 0.0000367

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TSC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs5901000; hg19: chr9-135773000;