rs2809243

Variant names:

• chr9-132894913-G-A
• rs2809243
• NM_000368.5:c.*1322C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132894913-G-A
• chr9-132894913-G-C
• chr9-132894913-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.*1322C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 231,208 control chromosomes in the GnomAD database, including 39,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24342 hom., cov: 31)
  • Exomes 𝑓: 0.61 (14745 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.304
• Publications: 16 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-132894913-G-A is Benign according to our data. Variant chr9-132894913-G-A is described in ClinVar as Benign. ClinVar VariationId is 365479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.*1322C>T		3_prime_UTR	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.*1322C>T		3_prime_UTR	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.*1322C>T		3_prime_UTR	Exon 23 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.*1322C>T		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.*1322C>T		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.*1322C>T		3_prime_UTR	Exon 23 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84402 AN: 151786 Hom.: 24315 Cov.: 31

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.551

GnomAD4 exome AF: 0.607 AC: 48155 AN: 79302 Hom.: 14745 Cov.: 0 AF XY: 0.611 AC XY: 22292 AN XY: 36488

African (AFR) AF: 0.395 AC: 1505 AN: 3814

American (AMR) AF: 0.587 AC: 1434 AN: 2442

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 3463 AN: 5030

East Asian (EAS) AF: 0.600 AC: 6717 AN: 11198

South Asian (SAS) AF: 0.642 AC: 434 AN: 676

European-Finnish (FIN) AF: 0.591 AC: 39 AN: 66

Middle Eastern (MID) AF: 0.572 AC: 279 AN: 488

European-Non Finnish (NFE) AF: 0.619 AC: 30322 AN: 48960

Other (OTH) AF: 0.598 AC: 3962 AN: 6628

GnomAD4 genome AF: 0.556 AC: 84479 AN: 151906 Hom.: 24342 Cov.: 31 AF XY: 0.560 AC XY: 41550 AN XY: 74202

African (AFR) AF: 0.396 AC: 16388 AN: 41400

American (AMR) AF: 0.603 AC: 9216 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2384 AN: 3466

East Asian (EAS) AF: 0.598 AC: 3068 AN: 5134

South Asian (SAS) AF: 0.676 AC: 3255 AN: 4816

European-Finnish (FIN) AF: 0.604 AC: 6362 AN: 10540

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41928 AN: 67948

Other (OTH) AF: 0.555 AC: 1170 AN: 2108

Alfa AF: 0.596 Hom.: 53939

Bravo AF: 0.546

Asia WGS AF: 0.628 AC: 2184 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	not provided (1)
-	-	1	Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.9
DANN	Benign	0.79
PhyloP100		-0.30
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: rs2809243; hg19: chr9-135770300;