rs11243929

Variant names:

• chr9-132898777-T-C
• rs11243929
• NM_000368.5:c.2626-1167A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000368.5(TSC1):​c.2626-1167A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,036 control chromosomes in the GnomAD database, including 5,221 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 0.25 (5221 hom., cov: 32)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 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.2626-1167A>G		intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.2626-1167A>G		intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.2626-1167A>G		intron	N/A	NP_001393522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-1167A>G		intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2626-1167A>G		intron	N/A	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2626-1167A>G		intron	N/A	ENSP00000495158.1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37660 AN: 151918 Hom.: 5205 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.0856

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.232

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

GnomAD4 genome AF: 0.248 AC: 37707 AN: 152036 Hom.: 5221 Cov.: 32 AF XY: 0.239 AC XY: 17793 AN XY: 74332

African (AFR) AF: 0.386 AC: 15984 AN: 41434

American (AMR) AF: 0.167 AC: 2559 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 671 AN: 3464

East Asian (EAS) AF: 0.0858 AC: 444 AN: 5176

South Asian (SAS) AF: 0.124 AC: 595 AN: 4812

European-Finnish (FIN) AF: 0.156 AC: 1656 AN: 10584

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.222 AC: 15057 AN: 67966

Other (OTH) AF: 0.236 AC: 498 AN: 2110

Alfa AF: 0.224 Hom.: 5066

Bravo AF: 0.256

Asia WGS AF: 0.150 AC: 522 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.9
DANN	Benign	0.49
PhyloP100		-0.098
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: rs11243929; hg19: chr9-135774164;