rs760737807

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000368.5(TSC1):c.2626-3_2626-2insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000448 in 914,826 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000069 ( 0 hom., cov: 14)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

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: Benign. The variant received -8 ACMG points.

BP6

Variant 9-132897612-T-TA is Benign according to our data. Variant chr9-132897612-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 802523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.2626-3_2626-2insT		splice_region_variant, intron_variant	Intron 20 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 link	c.2626-3_2626-2insT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4 link	c.2626-3_2626-2insT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes

AF:

0.0000687

AC:

AN:

43664

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00169

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000676

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000336

AC:

AN:

116050

AF XY:

0.000285

show subpopulations

Gnomad AFR exome

AF:

0.000227

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000709

Gnomad EAS exome

AF:

0.00112

Gnomad FIN exome

AF:

0.000130

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.000890

GnomAD4 exome

AF:

0.000467

AC:

407

AN:

871124

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

211

AN XY:

438666

show subpopulations

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

African (AFR)

AF:

0.000382

AC:

AN:

23534

American (AMR)

AF:

0.000924

AC:

AN:

22720

Ashkenazi Jewish (ASJ)

AF:

0.000390

AC:

AN:

15372

East Asian (EAS)

AF:

0.000737

AC:

AN:

29832

South Asian (SAS)

AF:

0.00177

AC:

AN:

41816

European-Finnish (FIN)

AF:

0.000698

AC:

AN:

28642

Middle Eastern (MID)

AF:

0.000311

AC:

AN:

3220

European-Non Finnish (NFE)

AF:

0.000352

AC:

235

AN:

668560

Other (OTH)

AF:

0.000508

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: 0.322

Heterozygous variant carriers

119

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

AF:

0.0000686

AC:

AN:

43702

Hom.:

Cov.:

AF XY:

0.0000491

AC XY:

AN XY:

20368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17812

American (AMR)

AF:

0.00

AC:

AN:

3378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

714

East Asian (EAS)

AF:

0.00170

AC:

AN:

1178

South Asian (SAS)

AF:

0.00

AC:

AN:

862

European-Finnish (FIN)

AF:

0.000676

AC:

AN:

1480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

17422

Other (OTH)

AF:

0.00

AC:

AN:

546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 1

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tuberous sclerosis syndrome

Benign:1

Nov 20, 2023

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over