9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAA

Variant names:

• chr9-132897613-GA-G
• rs5901000
• NM_000368.5:c.2626-4delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000368.5(TSC1):​c.2626-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.058 (147 hom., cov: 0)
  • Exomes 𝑓: 0.11 (18 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15 O:1
• 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 -9 ACMG points.

• BP6: Variant 9-132897613-GA-G is Benign according to our data. Variant chr9-132897613-GA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48983.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0615 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.2626-4delT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-4delT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-4delT		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.2626-4delT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-4delT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-4delT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 6083 AN: 104014 Hom.: 147 Cov.: 0

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.0667

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.0856

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0590

GnomAD2 exomes AF: 0.210 AC: 21819 AN: 103824 AF XY: 0.208

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.107 AC: 128027 AN: 1199362 Hom.: 18 Cov.: 0 AF XY: 0.107 AC XY: 63386 AN XY: 594370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.168 AC: 4397 AN: 26202

American (AMR) AF: 0.129 AC: 3177 AN: 24578

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 2247 AN: 19366

East Asian (EAS) AF: 0.0999 AC: 3308 AN: 33102

South Asian (SAS) AF: 0.0811 AC: 5017 AN: 61854

European-Finnish (FIN) AF: 0.122 AC: 3809 AN: 31344

Middle Eastern (MID) AF: 0.161 AC: 706 AN: 4386

European-Non Finnish (NFE) AF: 0.105 AC: 99942 AN: 948990

Other (OTH) AF: 0.109 AC: 5424 AN: 49540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0585 AC: 6080 AN: 104014 Hom.: 147 Cov.: 0 AF XY: 0.0581 AC XY: 2818 AN XY: 48544

African (AFR) AF: 0.0601 AC: 1449 AN: 24112

American (AMR) AF: 0.0514 AC: 509 AN: 9912

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 245 AN: 2984

East Asian (EAS) AF: 0.0102 AC: 38 AN: 3710

South Asian (SAS) AF: 0.0347 AC: 103 AN: 2970

European-Finnish (FIN) AF: 0.0409 AC: 148 AN: 3620

Middle Eastern (MID) AF: 0.0750 AC: 15 AN: 200

European-Non Finnish (NFE) AF: 0.0633 AC: 3441 AN: 54402

Other (OTH) AF: 0.0607 AC: 84 AN: 1384

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Tuberous sclerosis 1 (4)
-	1	3	Tuberous sclerosis syndrome (5)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Isolated focal cortical dysplasia type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52
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: rs5901000; hg19: chr9-135773000; COSMIC: COSV53765160; COSMIC: COSV53765160;