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 -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. 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, 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 -20 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 VariationId is 365480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 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.*1275T>G		3_prime_UTR	Exon 23 of 23	NP_000359.1
	TSC1	NM_001406592.1		c.*1275T>G		3_prime_UTR	Exon 23 of 23	NP_001393521.1
	TSC1	NM_001406593.1		c.*1275T>G		3_prime_UTR	Exon 23 of 23	NP_001393522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.*1275T>G		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.*1275T>G		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.*1275T>G		3_prime_UTR	Exon 23 of 23	ENSP00000495158.1

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

ClinVar submissions as Germline

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	-0.84
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;