rs6597586

Variant names:

• chr9-132910725-T-C
• rs6597586
• NM_000368.5:c.1142-33A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132910725-T-C
• chr9-132910725-T-G

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.1142-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,106 control chromosomes in the GnomAD database, including 15,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.15 (1834 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13383 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: 0.194
• 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: 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-132910725-T-C is Benign according to our data. Variant chr9-132910725-T-C is described in ClinVar as Benign. ClinVar VariationId is 48747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 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.1142-33A>G		intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.1142-33A>G		intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.1142-33A>G		intron	N/A	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.1142-33A>G		intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.1142-33A>G		intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000493467.6	TSL:1	n.416-36A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22847 AN: 152062 Hom.: 1824 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0848

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.125 AC: 30855 AN: 246716 AF XY: 0.123

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0875

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.133 AC: 193632 AN: 1459926 Hom.: 13383 Cov.: 34 AF XY: 0.131 AC XY: 95332 AN XY: 726216

African (AFR) AF: 0.217 AC: 7252 AN: 33436

American (AMR) AF: 0.0890 AC: 3979 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3682 AN: 26136

East Asian (EAS) AF: 0.0710 AC: 2820 AN: 39700

South Asian (SAS) AF: 0.105 AC: 9037 AN: 86204

European-Finnish (FIN) AF: 0.104 AC: 5464 AN: 52760

Middle Eastern (MID) AF: 0.107 AC: 524 AN: 4876

European-Non Finnish (NFE) AF: 0.137 AC: 152800 AN: 1111808

Other (OTH) AF: 0.134 AC: 8074 AN: 60286

GnomAD4 genome AF: 0.150 AC: 22885 AN: 152180 Hom.: 1834 Cov.: 31 AF XY: 0.145 AC XY: 10782 AN XY: 74424

African (AFR) AF: 0.212 AC: 8816 AN: 41498

American (AMR) AF: 0.103 AC: 1576 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3470

East Asian (EAS) AF: 0.0850 AC: 441 AN: 5186

South Asian (SAS) AF: 0.104 AC: 503 AN: 4822

European-Finnish (FIN) AF: 0.103 AC: 1093 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9538 AN: 67998

Other (OTH) AF: 0.148 AC: 312 AN: 2114

Alfa AF: 0.139 Hom.: 2346

Bravo AF: 0.153

Asia WGS AF: 0.127 AC: 444 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Tuberous sclerosis 1 (1)
-	-	-	Malignant tumor of urinary bladder (1)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.78
DANN	Benign	0.72
PhyloP100		0.19
BranchPoint Hunter		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6597586; hg19: chr9-135786112; COSMIC: COSV53763254; COSMIC: COSV53763254;