rs1060503192
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000368.5(TSC1):c.2626-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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, splice_polypyrimidine_tract, intron
NM_000368.5 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.0002151
2
Clinical Significance
Conservation
PhyloP100: -0.387
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 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 id is 411211.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=3}. Variant chr9-132897613-G-A is described in Lovd as [Likely_benign]. Variant chr9-132897613-G-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00603 (626/103884) while in subpopulation EAS AF= 0.00756 (28/3706). AF 95% confidence interval is 0.00544. There are 0 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 14. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 626 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.2626-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.2626-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00601 AC: 624AN: 103884Hom.: 0 Cov.: 14
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0173 AC: 21610AN: 1245630Hom.: 15 Cov.: 27 AF XY: 0.0187 AC XY: 11567AN XY: 618726
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? AF: 0.00603 AC: 626AN: 103884Hom.: 0 Cov.: 14 AF XY: 0.00582 AC XY: 282AN XY: 48488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2018 | - - |
not provided Uncertain:1Benign:3
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | TSC1: BP4, BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
TSC1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 09, 2020 | 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
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 23, 2020 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at