chr13-23355579-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014363.6(SACS):c.1033C>T(p.Arg345Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014363.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152078Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251392Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135866
GnomAD4 exome AF: 0.000128 AC: 187AN: 1461880Hom.: 0 Cov.: 34 AF XY: 0.000139 AC XY: 101AN XY: 727242
GnomAD4 genome AF: 0.000105 AC: 16AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74280
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Uncertain:3
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The c.1033C>T (p.Arg345Trp) variant identified in the SACS gene substitutes a well conserved Arginine for Tryptophan at amino acid 345/4580 (exon 8/10). This variant is found with low frequency in gnomAD(v3.1.1)(16 heterozygotes, 0 homozygotes; allele frequency: 1.05e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL;score:0.6349) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:411689), and to our current knowledge has not been reported in affected individuals in the literature. The p.Arg345 residue is not within a mapped domain of SACS (UniProtKB:Q9NZJ4). Given the lack of compelling evidence for its pathogenicity, the c.1033C>T (p.Arg345Trp) variant identified in the SACS gene is reported as a Variant of Uncertain Significance. -
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not specified Uncertain:1
Variant summary: SACS c.1033C>T (p.Arg345Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251392 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Charlevoix-Saguenay spastic ataxia, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1033C>T in individuals affected with Charlevoix-Saguenay spastic ataxia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 411689). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The c.1033C>T (p.R345W) alteration is located in exon 8 (coding exon 7) of the SACS gene. This alteration results from a C to T substitution at nucleotide position 1033, causing the arginine (R) at amino acid position 345 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.006% (15/251392) total alleles studied. The highest observed frequency was 0.02% (6/30612) of South Asian alleles. This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Spastic paraplegia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at