9-132897613-GAAAAAAAAAAAA-GAAAAAAA

Variant names:

• chr9-132897613-GAAAAA-G
• rs5901000
• NM_000368.5:c.2626-8_2626-4delTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000368.5(TSC1):​c.2626-8_2626-4delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000718 in 1,253,568 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18
• Publications: 7 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 -8 ACMG points.

• BP6: Variant 9-132897613-GAAAAA-G is Benign according to our data. Variant chr9-132897613-GAAAAA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1692402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2626-8_2626-4delTTTTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-8_2626-4delTTTTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-8_2626-4delTTTTT		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.2626-8_2626-4delTTTTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-8_2626-4delTTTTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-8_2626-4delTTTTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000718 AC: 90 AN: 1253568 Hom.: 0 AF XY: 0.0000658 AC XY: 41 AN XY: 623066

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

African (AFR) AF: 0.000177 AC: 5 AN: 28198

American (AMR) AF: 0.0000734 AC: 2 AN: 27244

Ashkenazi Jewish (ASJ) AF: 0.0000495 AC: 1 AN: 20200

East Asian (EAS) AF: 0.0000846 AC: 3 AN: 35446

South Asian (SAS) AF: 0.0000305 AC: 2 AN: 65636

European-Finnish (FIN) AF: 0.000121 AC: 4 AN: 33122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4556

European-Non Finnish (NFE) AF: 0.0000699 AC: 69 AN: 987422

Other (OTH) AF: 0.0000773 AC: 4 AN: 51744

⚠️ 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 Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)
-	-	1	TSC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=76/24	polymorphism

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;