rs2519757

Variant names:

• chr9-132903480-T-C
• rs2519757
• NM_000368.5:c.2208+171A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000368.5(TSC1):​c.2208+171A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 152,300 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.045 (212 hom., cov: 32)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-132903480-T-C is Benign according to our data. Variant chr9-132903480-T-C is described in ClinVar as Benign. ClinVar VariationId is 677248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0664 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2208+171A>G		intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.2208+171A>G		intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.2208+171A>G		intron	N/A	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2208+171A>G		intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2208+171A>G		intron	N/A	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2208+171A>G		intron	N/A	ENSP00000495158.1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6901 AN: 152182 Hom.: 212 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0680

Gnomad OTH AF: 0.0564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0453 AC: 6898 AN: 152300 Hom.: 212 Cov.: 32 AF XY: 0.0427 AC XY: 3177 AN XY: 74476

African (AFR) AF: 0.0165 AC: 685 AN: 41564

American (AMR) AF: 0.0550 AC: 842 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4822

European-Finnish (FIN) AF: 0.0252 AC: 268 AN: 10622

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0680 AC: 4626 AN: 68014

Other (OTH) AF: 0.0558 AC: 118 AN: 2114

Alfa AF: 0.0584 Hom.: 265

Bravo AF: 0.0465

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2519757; hg19: chr9-135778867;