rs2250057

Positions:

• chr9-132899816-C-A
• chr9-132899816-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000368.5(TSC1):​c.2625+899G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 151,988 control chromosomes in the GnomAD database, including 28,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (28019 hom., cov: 31)
  • Exomes 𝑓: 0.68 (8 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.960

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]

TSC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2625+899G>T		intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2625+899G>T		intron_variant		1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2625+899G>T		intron_variant		3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.606 AC: 91962 AN: 151842 Hom.: 28000 Cov.: 31

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.679 AC: 19 AN: 28 Hom.: 8 Cov.: 0 AF XY: 0.727 AC XY: 16 AN XY: 22

Gnomad4 ASJ exome AF: 1.00

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.606 AC: 92026 AN: 151960 Hom.: 28019 Cov.: 31 AF XY: 0.609 AC XY: 45217 AN XY: 74284

Gnomad4 AFR AF: 0.537

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.709

Gnomad4 EAS AF: 0.638

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.661

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.597

Alfa AF: 0.624 Hom.: 31014

Bravo AF: 0.589

Asia WGS AF: 0.680 AC: 2364 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.013
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2250057; hg19: chr9-135775203;