rs2519757

Variant names:

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

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.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

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=-0.91).
• BP6: Variant 9-132903480-T-C is Benign according to our data. Variant chr9-132903480-T-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2208+171A>G		intron_variant	Intron 17 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2208+171A>G		intron_variant	Intron 17 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2208+171A>G		intron_variant	Intron 18 of 23	3		ENSP00000495533.2

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

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0550

Gnomad4 ASJ AF: 0.0646

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0680

Gnomad4 OTH AF: 0.0558

Alfa AF: 0.0584 Hom.: 167

Bravo AF: 0.0465

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2519757; hg19: chr9-135778867;