rs281865120
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.12160C>T(p.Gln4054*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,820 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 Likely pathogenic (★★).
Frequency
Consequence
NM_014363.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250398Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135352
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461658Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727124
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:6Other:1
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Variant summary: SACS c.12160C>T (p.Gln4054X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in HGMD in association with Spastic ataxia, Charlevoix-Saguenay. The variant allele was found at a frequency of 1.6e-05 in 250398 control chromosomes. c.12160C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (eg. Vermeer_2008, Vermeer_2009). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:5
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Nonsense variant predicted to result in protein truncation, as the last 526 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23280630, 27288452, 18465152, 31589614) -
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Spastic paraplegia Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln4054*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 526 amino acid(s) of the SACS protein. This variant is present in population databases (rs281865120, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 18465152, 27288452). ClinVar contains an entry for this variant (Variation ID: 38458). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg4325*, p.Glu4309*, p.Phe4352Leufs*11) have been determined to be pathogenic (PMID: 16944349, 23497566, 26288984). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at