NM_000368.5:c.2626-3_2626-2insTTT

Variant names:

• chr9-132897612-T-TAAA
• rs760737807
• NM_000368.5:c.2626-3_2626-2insTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000368.5(TSC1):​c.2626-3_2626-2insTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 14)
  • Exomes 𝑓: 0.00049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.387
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.2626-3_2626-2insTTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-3_2626-2insTTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-3_2626-2insTTT		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.2626-3_2626-2insTTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-3_2626-2insTTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-3_2626-2insTTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 5 AN: 43656 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.000112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000115

Gnomad OTH AF: 0.00185

GnomAD2 exomes AF: 0.000483 AC: 56 AN: 116050 AF XY: 0.000480

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000676

Gnomad ASJ exome AF: 0.000236

Gnomad EAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00134

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000493 AC: 427 AN: 866556 Hom.: 0 Cov.: 27 AF XY: 0.000555 AC XY: 242 AN XY: 436108

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

African (AFR) AF: 0.000213 AC: 5 AN: 23494

American (AMR) AF: 0.000803 AC: 18 AN: 22404

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 9 AN: 15288

East Asian (EAS) AF: 0.000674 AC: 20 AN: 29656

South Asian (SAS) AF: 0.00230 AC: 94 AN: 40856

European-Finnish (FIN) AF: 0.000633 AC: 18 AN: 28438

Middle Eastern (MID) AF: 0.000623 AC: 2 AN: 3212

European-Non Finnish (NFE) AF: 0.000357 AC: 238 AN: 665994

Other (OTH) AF: 0.000618 AC: 23 AN: 37214

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000115 AC: 5 AN: 43656 Hom.: 0 Cov.: 14 AF XY: 0.000148 AC XY: 3 AN XY: 20336

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

African (AFR) AF: 0.000112 AC: 2 AN: 17782

American (AMR) AF: 0.00 AC: 0 AN: 3364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 714

East Asian (EAS) AF: 0.00 AC: 0 AN: 1188

South Asian (SAS) AF: 0.00 AC: 0 AN: 862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.000115 AC: 2 AN: 17412

Other (OTH) AF: 0.00185 AC: 1 AN: 542

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs760737807; hg19: chr9-135772999;