Genetic Variant TSC1:c.2626-3_2626-2insTT (chr9-132897612-T-TAA) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

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

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 14)

Exomes 𝑓: 0.0025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.387

Publications

0 publications found

Variant links:

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

TSC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 9-132897612-T-TAA is Benign according to our data. Variant chr9-132897612-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 466089.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TSC1	NM_000368.5	MANE Select	c.2626-3_2626-2insTT	splice_region intron	N/A	NP_000359.1	Q92574-1
TSC1	NM_001406592.1		c.2626-3_2626-2insTT	splice_region intron	N/A	NP_001393521.1	X5D9D2
TSC1	NM_001406593.1		c.2626-3_2626-2insTT	splice_region intron	N/A	NP_001393522.1	Q92574-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-3_2626-2insTT	splice_region intron	N/A	ENSP00000298552.3	Q92574-1
TSC1	ENST00000490179.4	TSL:3	c.2626-3_2626-2insTT	splice_region intron	N/A	ENSP00000495533.2	Q92574-1
TSC1	ENST00000643875.1		c.2626-3_2626-2insTT	splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes

AF:

0.00260

AC:

112

AN:

43072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000395

Gnomad AMI

AF:

0.00870

Gnomad AMR

AF:

0.00450

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00272

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00423

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00165

AC:

192

AN:

116050

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.000341

Gnomad AMR exome

AF:

0.00363

Gnomad ASJ exome

AF:

0.000945

Gnomad EAS exome

AF:

0.00405

Gnomad FIN exome

AF:

0.000391

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00312

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00249

AC:

2157

AN:

867672

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1156

AN XY:

436752

show subpopulations

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

African (AFR)

AF:

0.000808

AC:

AN:

23502

American (AMR)

AF:

0.00488

AC:

110

AN:

22532

Ashkenazi Jewish (ASJ)

AF:

0.00392

AC:

AN:

15296

East Asian (EAS)

AF:

0.00273

AC:

AN:

29698

South Asian (SAS)

AF:

0.0114

AC:

469

AN:

41094

European-Finnish (FIN)

AF:

0.00376

AC:

107

AN:

28490

Middle Eastern (MID)

AF:

0.00280

AC:

AN:

3212

European-Non Finnish (NFE)

AF:

0.00182

AC:

1211

AN:

666592

Other (OTH)

AF:

0.00244

AC:

AN:

37256

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.295

Heterozygous variant carriers

170

340

511

681

851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00260

AC:

112

AN:

43112

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

AN XY:

20132

show subpopulations

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

African (AFR)

AF:

0.000394

AC:

AN:

17752

American (AMR)

AF:

0.00449

AC:

AN:

3340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

678

East Asian (EAS)

AF:

0.00523

AC:

AN:

1148

South Asian (SAS)

AF:

0.00704

AC:

AN:

852

European-Finnish (FIN)

AF:

0.00272

AC:

AN:

1468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00423

AC:

AN:

17034

Other (OTH)

AF:

0.00

AC:

AN:

532

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over