rs45468995
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000368.5(TSC1):c.2865C>T(p.Thr955Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,154 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000368.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 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.2865C>T | p.Thr955Thr | synonymous_variant | Exon 22 of 23 | 1 | NM_000368.5 | ENSP00000298552.3 | ||
TSC1 | ENST00000490179.4 | c.2865C>T | p.Thr955Thr | synonymous_variant | Exon 23 of 24 | 3 | ENSP00000495533.2 |
Frequencies
GnomAD3 genomes AF: 0.00187 AC: 284AN: 152146Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00161 AC: 405AN: 251496Hom.: 1 AF XY: 0.00157 AC XY: 213AN XY: 135922
GnomAD4 exome AF: 0.00259 AC: 3792AN: 1461890Hom.: 8 Cov.: 33 AF XY: 0.00253 AC XY: 1842AN XY: 727248
GnomAD4 genome AF: 0.00187 AC: 284AN: 152264Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128AN XY: 74458
ClinVar
Submissions by phenotype
not specified Benign:10
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Thr955Thr in exon 22 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.2% (20/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs45468995). -
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Tuberous sclerosis 1 Benign:6
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not provided Benign:2
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TSC1: BP4, BP7 -
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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Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Benign:1
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Isolated focal cortical dysplasia type II Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at