rs374656811
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_015046.7(SETX):c.5949+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00122 in 1,613,814 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_015046.7 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SETX | ENST00000224140.6 | c.5949+5G>A | splice_region_variant, intron_variant | Intron 14 of 25 | 1 | NM_015046.7 | ENSP00000224140.5 | |||
| SETX | ENST00000436441.5 | c.675+5G>A | splice_region_variant, intron_variant | Intron 4 of 16 | 5 | ENSP00000409143.1 |
Frequencies
GnomAD3 genomes 0.000756 AC: 115AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000748 AC: 188AN: 251436Hom.: 0 AF XY: 0.000714 AC XY: 97AN XY: 135892
GnomAD4 exome AF: 0.00127 AC: 1857AN: 1461684Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 876AN XY: 727156
GnomAD4 genome 0.000756 AC: 115AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.000700 AC XY: 52AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:4
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The SETX c.5949+5G>A variant (rs374656811), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 488730). This variant is found in the non-Finnish European population with an overall allele frequency of 0.13% (174/129164 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although RNA studies would be required to confirm this. Given the lack of clinical and functional data, the significance of the c.5949+5G>A variant is uncertain at this time. -
BS1 -
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing -
not specified Benign:2
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Variant summary: SETX c.5949+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site, two predict the variant weakens a 5' donor site, and one predicts no impact on splicing. Two tools also predict the variant abolishes a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 1613814 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SETX causing autosomal recessive spinocerebellar ataxia with axonal neuropathy 2 (0.0012). To our knowledge, no occurrence of c.5949+5G>A in individuals affected with autosomal recessive spinocerebellar ataxia with axonal neuropathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 488730). Based on the evidence outlined above, the variant was classified as likely benign. -
Inborn genetic diseases Uncertain:1
The c.5949+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the SETX gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this variant is unlikely to be causative of juvenile amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain. -
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Uncertain:1
This sequence change falls in intron 14 of the SETX gene. It does not directly change the encoded amino acid sequence of the SETX protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374656811, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SETX-related conditions. ClinVar contains an entry for this variant (Variation ID: 488730). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary spastic paraplegia Uncertain:1
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Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Amyotrophic lateral sclerosis type 4 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
SETX-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at