rs1156566314
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.10939G>T(p.Glu3647Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,216 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. E3647E) 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.10939G>T | p.Glu3647Ter | stop_gained | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.10939G>T | p.Glu3647Ter | stop_gained | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74372
ClinVar
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 21, 2020 | This sequence change results in a premature translational stop signal in the SACS gene (p.Glu3647*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 933 amino acids of the SACS protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the SACS protein. Other variant(s) that disrupt this region (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with SACS-related conditions. This variant is not present in population databases (ExAC no frequency). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 16, 2023 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at