9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAAAAAAA

Variant names:

• chr9-132897613-G-GAAAA
• rs5901000
• NM_000368.5:c.2626-7_2626-4dupTTTT

Variant summary

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

The NM_000368.5(TSC1):​c.2626-7_2626-4dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0038 (10 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -8 ACMG points.

• BP6: Variant 9-132897613-G-GAAAA is Benign according to our data. Variant chr9-132897613-G-GAAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1692398.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.2626-7_2626-4dupTTTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-7_2626-4dupTTTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-7_2626-4dupTTTT		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.2626-7_2626-4dupTTTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-7_2626-4dupTTTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-7_2626-4dupTTTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 14 AN: 104094 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000276

Gnomad MID AF: 0.00450

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00383 AC: 4777 AN: 1247732 Hom.: 10 Cov.: 0 AF XY: 0.00398 AC XY: 2467 AN XY: 619954

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

African (AFR) AF: 0.00366 AC: 103 AN: 28120

American (AMR) AF: 0.00744 AC: 201 AN: 27028

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 114 AN: 20098

East Asian (EAS) AF: 0.00480 AC: 169 AN: 35240

South Asian (SAS) AF: 0.0117 AC: 754 AN: 64696

European-Finnish (FIN) AF: 0.00416 AC: 137 AN: 32960

Middle Eastern (MID) AF: 0.00395 AC: 18 AN: 4552

European-Non Finnish (NFE) AF: 0.00312 AC: 3069 AN: 983526

Other (OTH) AF: 0.00412 AC: 212 AN: 51512

⚠️ 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: 0.000134 AC: 14 AN: 104094 Hom.: 1 Cov.: 0 AF XY: 0.000144 AC XY: 7 AN XY: 48580

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

African (AFR) AF: 0.0000829 AC: 2 AN: 24134

American (AMR) AF: 0.000101 AC: 1 AN: 9916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2992

East Asian (EAS) AF: 0.00 AC: 0 AN: 3710

South Asian (SAS) AF: 0.00 AC: 0 AN: 2974

European-Finnish (FIN) AF: 0.000276 AC: 1 AN: 3618

Middle Eastern (MID) AF: 0.00500 AC: 1 AN: 200

European-Non Finnish (NFE) AF: 0.000165 AC: 9 AN: 54440

Other (OTH) AF: 0.00 AC: 0 AN: 1386

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0103046), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52
Mutation Taster		=100/0	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;