GeneBe

ENST00000403810.6:c.1032A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The ENST00000403810.6(TSC1):ā€‹c.1032A>Gā€‹(p.Val344Val) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000688 in 1,452,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

TSC1
ENST00000403810.6 synonymous

Scores

2
Splicing: ADA: 0.9998
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 4.70

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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 9-132911450-T-C is Pathogenic according to our data. Variant chr9-132911450-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547823.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000403810.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TSC1
NM_000368.5
MANE Select
c.1029+3A>G
splice_region intron
N/ANP_000359.1Q92574-1
TSC1
NM_001406629.1
c.-62A>G
5_prime_UTR
Exon 9 of 22NP_001393558.1
TSC1
NM_001406630.1
c.-62A>G
5_prime_UTR
Exon 10 of 23NP_001393559.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TSC1
ENST00000403810.6
TSL:1
c.1032A>Gp.Val344Val
synonymous
Exon 10 of 10ENSP00000386093.1Q86WV8
TSC1
ENST00000298552.9
TSL:1 MANE Select
c.1029+3A>G
splice_region intron
N/AENSP00000298552.3Q92574-1
TSC1
ENST00000490179.4
TSL:3
c.1029+3A>G
splice_region intron
N/AENSP00000495533.2Q92574-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1452462
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
723284
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33274
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26074
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39656
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86076
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
9.06e-7
AC:
1
AN:
1103388
Other (OTH)
AF:
0.00
AC:
0
AN:
60108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31

ClinVar

ClinVar submissions
Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
2
-
not provided (2)
1
1
-
Tuberous sclerosis 1 (2)
1
-
-
Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
CADD
Benign
19
DANN
Benign
0.96
PhyloP100
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.82
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.82
Position offset: 3

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

Publications

Other links and lift over

dbSNP: rs1554817334; hg19: chr9-135786837; API