chr9-132311819-TTCTC-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_015046.7(SETX):c.5308_5311delGAGA(p.Glu1770IlefsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015046.7 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SETX | ENST00000224140.6 | c.5308_5311delGAGA | p.Glu1770IlefsTer15 | frameshift_variant | Exon 11 of 26 | 1 | NM_015046.7 | ENSP00000224140.5 | ||
SETX | ENST00000436441.5 | c.34_37delGAGA | p.Glu12IlefsTer15 | frameshift_variant | Exon 1 of 17 | 5 | ENSP00000409143.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251016Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135704
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461450Hom.: 0 AF XY: 0.0000316 AC XY: 23AN XY: 727016
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74502
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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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). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31656689, 31493945, 18405395, 33624863, 29858556, 19696032, 30560021, 27528516) -
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Pathogenic:2
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Abnormal central motor function Pathogenic:1
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Amyotrophic lateral sclerosis Pathogenic:1
Allele frequency for the Glu1770Ilefs*15 variant in SETX was 0.000075 in ALS cases and 0 in controls within the Project MinE ALS case-control cohort, which favors evidence supporting our criteria to be classified as likely pathogenic -
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Glu1770Ilefs*15) in the SETX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETX are known to be pathogenic (PMID: 14770181). This variant is present in population databases (rs750959420, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal recessive cerebellar ataxia (PMID: 18405395). ClinVar contains an entry for this variant (Variation ID: 448333). For these reasons, this variant has been classified as Pathogenic. -
SETX-related disorder Pathogenic:1
The SETX c.5308_5311delGAGA variant is predicted to result in a frameshift and premature protein termination (p.Glu1770Ilefs*15). This variant was reported in the homozygous state in multiple individuals with autosomal recessive spinocerebellar ataxia and was found to segregate with disorder in at least two unrelated families (Nicolaou et al. 2008. PubMed ID: 18405395; Algahtani et al. 2018. PubMed ID: 30560021; Table S1, Vural et al. 2021. PubMed ID: 33624863). This variant was also documented along with a canonical splice variant in an individual with autosomal recessive spinocerebellar ataxia (Marelliet al. 2016. PubMed ID: 27528516). None of the heterozygous carriers of this variant were reported to be symptomatic. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in SETX are expected to be pathogenic. This variant is interpreted as pathogenic. -
Cerebellar ataxia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at