9-132929522-G-A

Variant names:

• chr9-132929522-G-A
• rs3827665
• NM_000368.5:c.-80-570C>T

Variant summary

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

The NM_000368.5(TSC1):​c.-80-570C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0922 in 152,182 control chromosomes in the GnomAD database, including 638 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 0.092 (638 hom., cov: 32)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 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.-80-570C>T		intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.-80-570C>T		intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.-80-570C>T		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.-80-570C>T		intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.-80-570C>T		intron	N/A	ENSP00000495533.2
	TSC1	ENST00000403810.6	TSL:1	c.-80-570C>T		intron	N/A	ENSP00000386093.1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14019 AN: 152062 Hom.: 637 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.0879

Gnomad SAS AF: 0.0783

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.0880

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

GnomAD4 genome AF: 0.0922 AC: 14030 AN: 152182 Hom.: 638 Cov.: 32 AF XY: 0.0894 AC XY: 6652 AN XY: 74432

African (AFR) AF: 0.107 AC: 4429 AN: 41490

American (AMR) AF: 0.0576 AC: 880 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 268 AN: 3468

East Asian (EAS) AF: 0.0881 AC: 456 AN: 5178

South Asian (SAS) AF: 0.0779 AC: 376 AN: 4826

European-Finnish (FIN) AF: 0.0861 AC: 913 AN: 10608

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0951 AC: 6470 AN: 68010

Other (OTH) AF: 0.0888 AC: 188 AN: 2116

Alfa AF: 0.100 Hom.: 129

Bravo AF: 0.0906

Asia WGS AF: 0.0880 AC: 306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.37
PhyloP100		-0.082
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: rs3827665; hg19: chr9-135804909;