rs760737807
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_000368.5(TSC1):c.2626-3_2626-2insT variant causes a splice region, splice polypyrimidine tract, 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. 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, splice_polypyrimidine_tract, intron
NM_000368.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
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 -16 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 id is 802523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000467 (407/871124) while in subpopulation SAS AF= 0.00177 (74/41816). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4_exome. There are 211 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
BS2
?
High AC in GnomAdExome4 at 407 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.2626-3_2626-2insT | 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.2626-3_2626-2insT | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000687 AC: 3AN: 43664Hom.: 0 Cov.: 14
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GnomAD4 exome AF: 0.000467 AC: 407AN: 871124Hom.: 0 Cov.: 27 AF XY: 0.000481 AC XY: 211AN XY: 438666
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GnomAD4 genome ? AF: 0.0000686 AC: 3AN: 43702Hom.: 0 Cov.: 14 AF XY: 0.0000491 AC XY: 1AN XY: 20368
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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
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | - - |
Tuberous sclerosis syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at