rs760737807

chr9-132897612-T-TAchr9-132897612-T-TAAchr9-132897612-T-TAAAchr9-132897612-T-TTA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000368.5(TSC1):c.2626-3_2626-2insT 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 0.000448 in 914,826 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000069 (0 hom., cov: 14)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -12 ACMG points.

• BP6: Variant 9-132897612-T-TA is Benign according to our data. Variant chr9-132897612-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 802523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000467 (407/871124) while in subpopulation SAS AF= 0.00177 (74/41816). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4_exome. There are 211 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000687 AC: 3 AN: 43664 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00169

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000676

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000467 AC: 407 AN: 871124 Hom.: 0 Cov.: 27 AF XY: 0.000481 AC XY: 211 AN XY: 438666

Gnomad4 AFR exome AF: 0.000382

Gnomad4 AMR exome AF: 0.000924

Gnomad4 ASJ exome AF: 0.000390

Gnomad4 EAS exome AF: 0.000737

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.000698

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.000508

GnomAD4 genome AF: 0.0000686 AC: 3 AN: 43702 Hom.: 0 Cov.: 14 AF XY: 0.0000491 AC XY: 1 AN XY: 20368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00170

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000676

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	- -

Tuberous sclerosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760737807; hg19: chr9-135772999; COSMIC: COSV53765632; COSMIC: COSV53765632;