rs118203599
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000368.5(TSC1):c.1907_1908del(p.Glu636GlyfsTer51) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E636E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000368.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.1907_1908del | p.Glu636GlyfsTer51 | frameshift_variant | 15/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.1907_1908del | p.Glu636GlyfsTer51 | frameshift_variant | 15/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2022 | Identified in patients with a clinical diagnosis of tuberous sclerosis complex in published literature (vanSlegtenhorst et al., 1997; TSC1 LOVD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11179759, 10363127, 30548481, 19419980, 9924605, 31444548, 22923433, 9242607) - |
Tuberous sclerosis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2019 | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu636Glyfs*51) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in a family affected with tuberous sclerosis complex (PMID: 9242607, 9924605). ClinVar contains an entry for this variant (Variation ID: 48852). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Malignant tumor of urinary bladder Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at