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

Variant names:

Variant summary

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

The NM_000368.5(TSC1):c.2626-3_2626-2insTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 871,106 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 14)

Exomes 𝑓: 0.00016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

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: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
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: 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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.000275

AC:

AN:

43668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000562

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000594

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00253

Gnomad SAS

AF:

0.00116

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000287

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

141

AN:

871106

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

AN XY:

438680

show subpopulations

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

African (AFR)

AF:

0.0000850

AC:

AN:

23542

American (AMR)

AF:

0.0000440

AC:

AN:

22732

Ashkenazi Jewish (ASJ)

AF:

0.000260

AC:

AN:

15370

East Asian (EAS)

AF:

0.000235

AC:

AN:

29834

South Asian (SAS)

AF:

0.0000955

AC:

AN:

41888

European-Finnish (FIN)

AF:

0.000314

AC:

AN:

28640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3218

European-Non Finnish (NFE)

AF:

0.000159

AC:

106

AN:

668454

Other (OTH)

AF:

0.000214

AC:

AN:

37428

⚠️ 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: 0.257

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000275

AC:

AN:

43706

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

AN XY:

20370

show subpopulations

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

African (AFR)

AF:

0.0000561

AC:

AN:

17820

American (AMR)

AF:

0.000592

AC:

AN:

3376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

714

East Asian (EAS)

AF:

0.00255

AC:

AN:

1176

South Asian (SAS)

AF:

0.00116

AC:

AN:

860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000287

AC:

AN:

17422

Other (OTH)

AF:

0.00

AC:

AN:

546

⚠️ 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: 0.275

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Isolated focal cortical dysplasia type II

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.39

Mutation Taster

=91/9

polymorphism

(source)

Splicing

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over