chr9-132892556-C-T

Variant names:

• chr9-132892556-C-T
• rs1050700
• NM_000368.5:c.*3679G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.*3679G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 233,098 control chromosomes in the GnomAD database, including 56,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36245 hom., cov: 32)
  • Exomes 𝑓: 0.71 (20694 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.68
• Publications: 18 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-132892556-C-T is Benign according to our data. Variant chr9-132892556-C-T is described in ClinVar as Benign. ClinVar VariationId is 365414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.799 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.*3679G>A		3_prime_UTR	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.*3679G>A		3_prime_UTR	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.*3679G>A		3_prime_UTR	Exon 23 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.*3679G>A		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.*3679G>A		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000646440.2		c.*3679G>A		3_prime_UTR	Exon 23 of 23	ENSP00000495830.2	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104476 AN: 151944 Hom.: 36217 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.671

GnomAD4 exome AF: 0.714 AC: 57832 AN: 81036 Hom.: 20694 Cov.: 0 AF XY: 0.716 AC XY: 26708 AN XY: 37282

African (AFR) AF: 0.619 AC: 2411 AN: 3896

American (AMR) AF: 0.634 AC: 1587 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 3846 AN: 5124

East Asian (EAS) AF: 0.798 AC: 9107 AN: 11410

South Asian (SAS) AF: 0.815 AC: 572 AN: 702

European-Finnish (FIN) AF: 0.750 AC: 42 AN: 56

Middle Eastern (MID) AF: 0.656 AC: 324 AN: 494

European-Non Finnish (NFE) AF: 0.703 AC: 35233 AN: 50086

Other (OTH) AF: 0.696 AC: 4710 AN: 6766

GnomAD4 genome AF: 0.688 AC: 104556 AN: 152062 Hom.: 36245 Cov.: 32 AF XY: 0.694 AC XY: 51582 AN XY: 74348

African (AFR) AF: 0.612 AC: 25384 AN: 41462

American (AMR) AF: 0.648 AC: 9899 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2574 AN: 3472

East Asian (EAS) AF: 0.810 AC: 4177 AN: 5158

South Asian (SAS) AF: 0.820 AC: 3954 AN: 4822

European-Finnish (FIN) AF: 0.795 AC: 8416 AN: 10584

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47920 AN: 67964

Other (OTH) AF: 0.675 AC: 1427 AN: 2114

Alfa AF: 0.693 Hom.: 61548

Bravo AF: 0.669

Asia WGS AF: 0.817 AC: 2840 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	not provided (1)
-	-	1	Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.73
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1050700; hg19: chr9-135767943;