rs2809244

Positions:

• chr9-132894960-A-C
• chr9-132894960-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000368.5(TSC1):​c.*1275T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 231,700 control chromosomes in the GnomAD database, including 63,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (42255 hom., cov: 31)
  • Exomes 𝑓: 0.74 (21713 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-132894960-A-C is Benign according to our data. Variant chr9-132894960-A-C is described in ClinVar as [Benign]. Clinvar id is 365480.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132894960-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.*1275T>G		3_prime_UTR_variant	23/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.*1275T>G		3_prime_UTR_variant	23/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113213 AN: 151904 Hom.: 42203 Cov.: 31

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.737

GnomAD4 exome AF: 0.738 AC: 58768 AN: 79678 Hom.: 21713 Cov.: 0 AF XY: 0.738 AC XY: 27053 AN XY: 36636

Gnomad4 AFR exome AF: 0.761

Gnomad4 AMR exome AF: 0.708

Gnomad4 ASJ exome AF: 0.826

Gnomad4 EAS exome AF: 0.650

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.739

Gnomad4 NFE exome AF: 0.747

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.745 AC: 113325 AN: 152022 Hom.: 42255 Cov.: 31 AF XY: 0.745 AC XY: 55335 AN XY: 74304

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.826

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.717

Gnomad4 NFE AF: 0.746

Gnomad4 OTH AF: 0.740

Alfa AF: 0.740 Hom.: 57188

Bravo AF: 0.743

Asia WGS AF: 0.764 AC: 2658 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.55

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: rs2809244; hg19: chr9-135770347;