Genetic Variant TSC1:c.210+33G>A (chr9-132927168-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000368.5(TSC1):c.210+33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00901 in 1,602,738 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0092 ( 106 hom. )

Consequence

TSC1
NM_000368.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -1.30

Publications

2 publications found

Variant links:

COSMIC-nc: COSV104404434

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 9-132927168-C-T is Benign according to our data. Variant chr9-132927168-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00742 (1130/152318) while in subpopulation SAS AF = 0.0199 (96/4832). AF 95% confidence interval is 0.0167. There are 12 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1130 AD gene.

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.210+33G>A	intron	N/A	NP_000359.1	Q92574-1
TSC1	NM_001406592.1		c.210+33G>A	intron	N/A	NP_001393521.1	X5D9D2
TSC1	NM_001406593.1		c.210+33G>A	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.210+33G>A	intron	N/A	ENSP00000298552.3	Q92574-1
TSC1	ENST00000490179.4	TSL:3	c.210+33G>A	intron	N/A	ENSP00000495533.2	Q92574-1
TSC1	ENST00000403810.6	TSL:1	c.210+33G>A	intron	N/A	ENSP00000386093.1	Q86WV8

Frequencies

GnomAD3 genomes

AF:

0.00742

AC:

1130

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00945

AC:

2317

AN:

245130

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.00127

Gnomad AMR exome

AF:

0.00796

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.00489

Gnomad FIN exome

AF:

0.00165

Gnomad NFE exome

AF:

0.00920

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00918

AC:

13315

AN:

1450420

Hom.:

106

Cov.:

AF XY:

0.00960

AC XY:

6929

AN XY:

721426

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33280

American (AMR)

AF:

0.00824

AC:

365

AN:

44304

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

614

AN:

25948

East Asian (EAS)

AF:

0.00162

AC:

AN:

39614

South Asian (SAS)

AF:

0.0201

AC:

1708

AN:

84784

European-Finnish (FIN)

AF:

0.00254

AC:

135

AN:

53164

Middle Eastern (MID)

AF:

0.00817

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00881

AC:

9725

AN:

1103572

Other (OTH)

AF:

0.0103

AC:

621

AN:

60004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

717

1435

2152

2870

3587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.00742

AC:

1130

AN:

152318

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41572

American (AMR)

AF:

0.00798

AC:

122

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3472

East Asian (EAS)

AF:

0.00521

AC:

AN:

5186

South Asian (SAS)

AF:

0.0199

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

686

AN:

68032

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00968

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Tuberous sclerosis 1 (2)

not specified (1)

Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.048

(source)

DANN

Benign

0.49

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over