rs2809244

Variant names:

• chr9-132894960-A-C
• rs2809244
• NM_000368.5:c.*1275T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• 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 rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.*1275T>G		3_prime_UTR_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.*1275T>G		3_prime_UTR_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.*1275T>G		3_prime_UTR_variant	Exon 24 of 24	3		ENSP00000495533.2

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

African (AFR) AF: 0.761 AC: 2924 AN: 3840

American (AMR) AF: 0.708 AC: 1741 AN: 2460

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 4136 AN: 5010

East Asian (EAS) AF: 0.650 AC: 7293 AN: 11216

South Asian (SAS) AF: 0.764 AC: 529 AN: 692

European-Finnish (FIN) AF: 0.739 AC: 102 AN: 138

Middle Eastern (MID) AF: 0.681 AC: 331 AN: 486

European-Non Finnish (NFE) AF: 0.747 AC: 36734 AN: 49202

Other (OTH) AF: 0.750 AC: 4978 AN: 6634

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

African (AFR) AF: 0.759 AC: 31476 AN: 41452

American (AMR) AF: 0.723 AC: 11043 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2862 AN: 3466

East Asian (EAS) AF: 0.690 AC: 3547 AN: 5140

South Asian (SAS) AF: 0.783 AC: 3778 AN: 4824

European-Finnish (FIN) AF: 0.717 AC: 7567 AN: 10560

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.746 AC: 50683 AN: 67984

Other (OTH) AF: 0.740 AC: 1565 AN: 2114

Alfa AF: 0.742 Hom.: 80822

Bravo AF: 0.743

Asia WGS AF: 0.764 AC: 2658 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tuberous sclerosis 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2809244; hg19: chr9-135770347;