chr9-132897613-G-GAA

Variant names:

• chr9-132897613-G-GAA
• rs5901000
• NM_000368.5:c.2626-5_2626-4dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.2626-5_2626-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (13696 hom., cov: 0)
  • Exomes 𝑓: 0.29 (4637 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.517
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 9-132897613-G-GAA is Benign according to our data. Variant chr9-132897613-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 495837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.636 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.2626-5_2626-4dupTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-5_2626-4dupTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-5_2626-4dupTT		splice_region 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.2626-5_2626-4dupTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-5_2626-4dupTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-5_2626-4dupTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 54441 AN: 103658 Hom.: 13696 Cov.: 0

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.536

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.526

GnomAD2 exomes AF: 0.178 AC: 18478 AN: 103824 AF XY: 0.180

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.199

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.190

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.289 AC: 343152 AN: 1187976 Hom.: 4637 Cov.: 0 AF XY: 0.286 AC XY: 168350 AN XY: 589650

African (AFR) AF: 0.135 AC: 3638 AN: 26946

American (AMR) AF: 0.192 AC: 4973 AN: 25888

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 5191 AN: 19044

East Asian (EAS) AF: 0.229 AC: 7582 AN: 33068

South Asian (SAS) AF: 0.259 AC: 16225 AN: 62740

European-Finnish (FIN) AF: 0.228 AC: 7078 AN: 31044

Middle Eastern (MID) AF: 0.220 AC: 961 AN: 4370

European-Non Finnish (NFE) AF: 0.303 AC: 284042 AN: 935986

Other (OTH) AF: 0.275 AC: 13462 AN: 48890

GnomAD4 genome AF: 0.525 AC: 54438 AN: 103658 Hom.: 13696 Cov.: 0 AF XY: 0.527 AC XY: 25475 AN XY: 48328

African (AFR) AF: 0.319 AC: 7665 AN: 24006

American (AMR) AF: 0.577 AC: 5681 AN: 9840

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 1900 AN: 2988

East Asian (EAS) AF: 0.611 AC: 2260 AN: 3696

South Asian (SAS) AF: 0.660 AC: 1952 AN: 2956

European-Finnish (FIN) AF: 0.558 AC: 1992 AN: 3572

Middle Eastern (MID) AF: 0.540 AC: 107 AN: 198

European-Non Finnish (NFE) AF: 0.585 AC: 31740 AN: 54300

Other (OTH) AF: 0.525 AC: 726 AN: 1384

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Tuberous sclerosis 1 (4)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)
-	-	1	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000; COSMIC: COSV105880820; COSMIC: COSV105880820;