rs141315518
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.12232C>T(p.Arg4078Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,718 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R4078R) has been classified as Likely benign.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.12232C>T | p.Arg4078Ter | stop_gained | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.12232C>T | p.Arg4078Ter | stop_gained | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250818Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135580
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461620Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727100
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152098Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74290
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 07, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 29, 2022 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Arg4078*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 502 amino acid(s) of the SACS protein. This variant is present in population databases (rs141315518, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with spastic ataxia of Charlevoix-Saguenay (PMID: 22816526). ClinVar contains an entry for this variant (Variation ID: 188867). This variant disrupts a region of the SACS protein in which other variant(s) (p.Tyr4538* ) have been determined to be pathogenic (Invitae). 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2022 | Reported in an individual with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), however segregation information was not provided (Prodi et al., 2013); Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22816526, 31589614) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at