NM_000368.5:c.2626-4dupT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000368.5(TSC1):​c.2626-4dupT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (26 hom., cov: 0)
  • Exomes 𝑓: 0.12 (1177 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• 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-GA is Benign according to our data. Variant chr9-132897613-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00816 (849/104078) while in subpopulation AFR AF = 0.0232 (560/24108). AF 95% confidence interval is 0.0216. There are 26 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 849 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.2626-4dupT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-4dupT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-4dupT		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.2626-4dupT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-4dupT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-4dupT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 843 AN: 104078 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00676

Gnomad ASJ AF: 0.00267

Gnomad EAS AF: 0.00941

Gnomad SAS AF: 0.00335

Gnomad FIN AF: 0.00277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.0116

GnomAD2 exomes AF: 0.170 AC: 17641 AN: 103824 AF XY: 0.173

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.116 AC: 140253 AN: 1205502 Hom.: 1177 Cov.: 0 AF XY: 0.117 AC XY: 69804 AN XY: 598492

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

African (AFR) AF: 0.0980 AC: 2672 AN: 27258

American (AMR) AF: 0.131 AC: 3448 AN: 26354

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 2481 AN: 19420

East Asian (EAS) AF: 0.122 AC: 4154 AN: 34050

South Asian (SAS) AF: 0.118 AC: 7473 AN: 63148

European-Finnish (FIN) AF: 0.122 AC: 3905 AN: 32066

Middle Eastern (MID) AF: 0.111 AC: 492 AN: 4416

European-Non Finnish (NFE) AF: 0.116 AC: 109822 AN: 948964

Other (OTH) AF: 0.117 AC: 5806 AN: 49826

⚠️ 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: 0.00816 AC: 849 AN: 104078 Hom.: 26 Cov.: 0 AF XY: 0.00842 AC XY: 409 AN XY: 48572

African (AFR) AF: 0.0232 AC: 560 AN: 24108

American (AMR) AF: 0.00696 AC: 69 AN: 9918

Ashkenazi Jewish (ASJ) AF: 0.00267 AC: 8 AN: 2992

East Asian (EAS) AF: 0.00944 AC: 35 AN: 3708

South Asian (SAS) AF: 0.00336 AC: 10 AN: 2974

European-Finnish (FIN) AF: 0.00277 AC: 10 AN: 3616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.00257 AC: 140 AN: 54454

Other (OTH) AF: 0.0123 AC: 17 AN: 1386

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Tuberous sclerosis 1 (4)
-	-	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		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: COSV53769953; COSMIC: COSV53769953;