rs29001665
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_015046.7(SETX):c.994C>T(p.Arg332Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,894 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_015046.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135878
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461762Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727176
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Pathogenic:3
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not provided Pathogenic:2
The R332W variant in the SETX gene has been reported previously in the compound heterozygous state, opposite of a second frameshift variant, in 2 siblings with cerebellar atrophy, elevated AFP and late childhood/early adult onset ocular apraxia and sensory motor neuropathy (Moreira et al., 2004). Roda et al. (2014) reported a Columbian female with severe cerebellar atrophy, elevated AFP and young adult onset of progressive sensory motor neuropathy, ataxia, muscle weakness and ocular apraxia who harbored the R332W variant with a second frameshift variant, assumed on the opposite SETX allele. The R332W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R332W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E327V, I331K) have been reported in the Human Gene Mutation Database in association with SETX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R332W as a pathogenic variant. -
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SETX-related disorder Pathogenic:1
The SETX c.994C>T variant is predicted to result in the amino acid substitution p.Arg332Trp. This variant has been reported in the compound heterozygous state in multiple individuals with ataxia-ocular apraxia (Table 1, Moreira et al. 2004. PubMed ID: 14770181; Figure 1, Roda et al. 2014. PubMed ID: 24814856). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. An in vitro experimental study using patient fibroblasts suggests this variant, in the compound heterozygous state, increases cells sensitivity to oxidative DNA damage (Figure 3, Roda et al. 2014. PubMed ID: 24814856). This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at