NM_000368.5:c.2626-3C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000368.5(TSC1):c.2626-3C>T 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. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0060 ( 0 hom., cov: 14)

Exomes 𝑓: 0.017 ( 15 hom. )

Failed GnomAD Quality Control

Consequence

TSC1
NM_000368.5 splice_region, intron

Scores

Splicing: ADA: 0.0002151

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: -0.387

Publications

2 publications found

Variant links:

COSMIC-nc: COSV108844505

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 9-132897613-G-A is Benign according to our data. Variant chr9-132897613-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411211.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.2626-3C>T		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.2626-3C>T		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4 link	c.2626-3C>T		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

624

AN:

103884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00552

Gnomad AMR

AF:

0.00606

Gnomad ASJ

AF:

0.00569

Gnomad EAS

AF:

0.00753

Gnomad SAS

AF:

0.00469

Gnomad FIN

AF:

0.00719

Gnomad MID

AF:

0.00450

Gnomad NFE

AF:

0.00583

Gnomad OTH

AF:

0.00655

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0173

AC:

21610

AN:

1245630

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

11567

AN XY:

618726

show subpopulations

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

African (AFR)

AF:

0.0104

AC:

292

AN:

27996

American (AMR)

AF:

0.0385

AC:

1032

AN:

26808

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

470

AN:

20060

East Asian (EAS)

AF:

0.0290

AC:

1017

AN:

35020

South Asian (SAS)

AF:

0.0484

AC:

3107

AN:

64250

European-Finnish (FIN)

AF:

0.0287

AC:

936

AN:

32648

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

4536

European-Non Finnish (NFE)

AF:

0.0139

AC:

13659

AN:

982922

Other (OTH)

AF:

0.0202

AC:

1037

AN:

51390

⚠️ 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: 0.354

Heterozygous variant carriers

1094

2188

3283

4377

5471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.00603

AC:

626

AN:

103884

Hom.:

Cov.:

AF XY:

0.00582

AC XY:

282

AN XY:

48488

show subpopulations

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

African (AFR)

AF:

0.00625

AC:

150

AN:

23994

American (AMR)

AF:

0.00616

AC:

AN:

9904

Ashkenazi Jewish (ASJ)

AF:

0.00569

AC:

AN:

2986

East Asian (EAS)

AF:

0.00756

AC:

AN:

3706

South Asian (SAS)

AF:

0.00471

AC:

AN:

2974

European-Finnish (FIN)

AF:

0.00719

AC:

AN:

3616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.00583

AC:

317

AN:

54394

Other (OTH)

AF:

0.00649

AC:

AN:

1386

⚠️ 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: 0.318

Heterozygous variant carriers

115

153

191

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC1: BP4, BS1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tuberous sclerosis 1

Uncertain:2Benign:1

Jan 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tuberous sclerosis syndrome

Benign:1

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSC1-related disorder

Benign:1

Dec 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hereditary cancer-predisposing syndrome

Benign:1

Jul 23, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.77

(source)

DANN

Benign

0.54

PhyloP100

-0.39

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00022

dbscSNV1_RF

Benign

0.098

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over