rs762947018
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.12973C>T(p.Arg4325Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,792 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 (โ โ ). Synonymous variant affecting the same amino acid position (i.e. R4325R) 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.12973C>T | p.Arg4325Ter | stop_gained | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.12973C>T | p.Arg4325Ter | stop_gained | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250012Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135174
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461792Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727192
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 28, 2024 | Criteria applied: PVS1,PM3_STR,PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 19, 2021 | NM_014363.4(SACS):c.12973C>T(R4325*) is a nonsense variant classified as pathogenic in the context of autosomal recessive spastic ataxia of Charlevoix-Saguenay. R4325* has been observed in cases with relevant disease (PMID: 16944349, 27142713, 21665375, 31475473). Functional assessments of this variant are not available in the literature. R4325* has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_014363.4(SACS):c.12973C>T(R4325*) is a nonsense variant variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 26, 2023 | - - |
Likely pathogenic, no assertion criteria provided | research | Department of Rehabilitation Medicine, Incheon St. Maryโs Hospital, College of Medicine, The Catholic University of Korea | Feb 11, 2019 | The proband has another variant, NM_014363.5: c.11101T>C (p.Trp3701Arg). - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change creates a premature translational stop signal (p.Arg4325*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 255 amino acid(s) of the SACS protein. This variant is present in population databases (rs762947018, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 16944349, 21993619, 23280630). ClinVar contains an entry for this variant (Variation ID: 188912). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at