rs118203400
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_001406626.1(TSC1):c.-310C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000589 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001406626.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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TSC1 | ENST00000298552.9 | c.568C>T | p.Arg190Cys | missense_variant | Exon 7 of 23 | 1 | NM_000368.5 | ENSP00000298552.3 | ||
TSC1 | ENST00000490179.4 | c.568C>T | p.Arg190Cys | missense_variant | Exon 8 of 24 | 3 | ENSP00000495533.2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251360Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135846
GnomAD4 exome AF: 0.0000622 AC: 91AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727244
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
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This variant is associated with the following publications: (PMID: 19747374, 21309039, 10227394, 23857276, 26517685) -
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Tuberous sclerosis 1 Benign:3
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Hereditary cancer-predisposing syndrome Benign:2
This alteration is classified as likely 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. -
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Tuberous sclerosis syndrome Benign:1Other:1
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TSC1-related disorder Uncertain:1
The TSC1 c.568C>T variant is predicted to result in the amino acid substitution p.Arg190Cys. This variant has been reported in individuals affected with tuberous sclerosis complex (Mozaffari et al. 2009. PubMed ID: 19747374; Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039). Functional studies showed the signals in cells expressing the TSC1 variant was not significantly different from the signal in cells expressing wild-type TSC1 and this variant was considered a neutral variant (Mozaffari et al. 2009. PubMed ID: 19747374). It was also identified in an individual with Lynch syndrome (Table S3, Jóri et al. 2015. PubMed ID: 26517685). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity ranging from benign to uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/49057/). An alternative variant at the same amino acid (p.Arg190Pro) has been reported causative in patients with tuberous sclerosis complex (Mozaffari et al. 2009. PubMed ID: 19747374; Table S1, Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at