9-132905852-A-G

Variant names:

• chr9-132905852-A-G
• rs118203567
• NM_000368.5:c.1726T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000368.5(TSC1):​c.1726T>C​(p.Leu576Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,318 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: TSC1 NM_000368.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:2
• Conservation: PhyloP100: -0.240
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-132905852-A-G is Benign according to our data. Variant chr9-132905852-A-G is described in ClinVar as Benign. ClinVar VariationId is 48821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00225 (343/152334) while in subpopulation EAS AF = 0.0512 (265/5178). AF 95% confidence interval is 0.0461. There are 10 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 343 AD gene.

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.1726T>C	p.Leu576Leu	synonymous	Exon 15 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.1726T>C	p.Leu576Leu	synonymous	Exon 15 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.1726T>C	p.Leu576Leu	synonymous	Exon 15 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.1726T>C	p.Leu576Leu	synonymous	Exon 15 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.1726T>C	p.Leu576Leu	synonymous	Exon 16 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.1726T>C	p.Leu576Leu	synonymous	Exon 15 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152216 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00401 AC: 1006 AN: 251086 AF XY: 0.00367

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0507

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00139 AC: 2026 AN: 1460984 Hom.: 47 Cov.: 31 AF XY: 0.00132 AC XY: 959 AN XY: 726638

African (AFR) AF: 0.000479 AC: 16 AN: 33428

American (AMR) AF: 0.000201 AC: 9 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0404 AC: 1602 AN: 39688

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111284

Other (OTH) AF: 0.00457 AC: 276 AN: 60358

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152334 Hom.: 10 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74498

African (AFR) AF: 0.000962 AC: 40 AN: 41574

American (AMR) AF: 0.00105 AC: 16 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.00241

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Tuberous sclerosis 1 (5)
-	-	2	not provided (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)
-	-	-	Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.9
DANN	Benign	0.45
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs118203567; hg19: chr9-135781239; COSMIC: COSV53768783; COSMIC: COSV53768783;