rs7874234

Variant names:

• chr9-132937614-C-T
• rs7874234
• NM_000368.5:c.-143-2519G>A

Variant summary

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

The NM_000368.5(TSC1):​c.-143-2519G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,088 control chromosomes in the GnomAD database, including 4,659 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 0.24 (4659 hom., cov: 32)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.778
• Publications: 13 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.-143-2519G>A		intron_variant	Intron 1 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.-143-2519G>A		intron_variant	Intron 1 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.-239-2519G>A		intron_variant	Intron 1 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36632 AN: 151970 Hom.: 4647 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.231

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

GnomAD4 genome AF: 0.241 AC: 36683 AN: 152088 Hom.: 4659 Cov.: 32 AF XY: 0.233 AC XY: 17347 AN XY: 74332

African (AFR) AF: 0.310 AC: 12845 AN: 41484

American (AMR) AF: 0.233 AC: 3560 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3466

East Asian (EAS) AF: 0.109 AC: 566 AN: 5180

South Asian (SAS) AF: 0.153 AC: 739 AN: 4816

European-Finnish (FIN) AF: 0.161 AC: 1700 AN: 10568

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15805 AN: 67974

Other (OTH) AF: 0.234 AC: 493 AN: 2108

Alfa AF: 0.238 Hom.: 7586

Bravo AF: 0.252

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.72
PhyloP100		-0.78
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: rs7874234; hg19: chr9-135813001;