9-132929348-T-C

Variant names:

• chr9-132929348-T-C
• rs3761840
• NM_000368.5:c.-80-396A>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.-80-396A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 151,934 control chromosomes in the GnomAD database, including 13,920 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 0.41 (13920 hom., cov: 32)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.-80-396A>G		intron_variant	Intron 2 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.-80-396A>G		intron_variant	Intron 2 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.-80-396A>G		intron_variant	Intron 3 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62662 AN: 151816 Hom.: 13918 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.413

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

GnomAD4 genome AF: 0.412 AC: 62672 AN: 151934 Hom.: 13920 Cov.: 32 AF XY: 0.421 AC XY: 31260 AN XY: 74242

African (AFR) AF: 0.236 AC: 9807 AN: 41528

American (AMR) AF: 0.434 AC: 6640 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1901 AN: 3470

East Asian (EAS) AF: 0.555 AC: 2865 AN: 5164

South Asian (SAS) AF: 0.603 AC: 2903 AN: 4818

European-Finnish (FIN) AF: 0.512 AC: 5344 AN: 10436

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31780 AN: 67916

Other (OTH) AF: 0.414 AC: 873 AN: 2110

Alfa AF: 0.446 Hom.: 48369

Bravo AF: 0.392

Asia WGS AF: 0.542 AC: 1881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.038
DANN	Benign	0.73
PhyloP100		-2.0
PromoterAI		0.012	Neutral
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: rs3761840; hg19: chr9-135804735;