rs534723946
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_015046.7(SETX):c.1504C>T(p.Arg502Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,192 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_015046.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETX | NM_015046.7 | c.1504C>T | p.Arg502Trp | missense_variant | 10/26 | ENST00000224140.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETX | ENST00000224140.6 | c.1504C>T | p.Arg502Trp | missense_variant | 10/26 | 1 | NM_015046.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000289 AC: 44AN: 152226Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000541 AC: 136AN: 251320Hom.: 0 AF XY: 0.000648 AC XY: 88AN XY: 135830
GnomAD4 exome AF: 0.000254 AC: 372AN: 1461848Hom.: 3 Cov.: 35 AF XY: 0.000326 AC XY: 237AN XY: 727216
GnomAD4 genome AF: 0.000289 AC: 44AN: 152344Hom.: 1 Cov.: 33 AF XY: 0.000389 AC XY: 29AN XY: 74500
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SETX p.Arg502Trp variant was identified in 2 of 310 proband chromosomes (frequency: 0.0065) from individuals with inherited peripheral neuropathies or amyotrophic lateral sclerosis (Drew_2015_PMID:25802885; Liu_2019_PMID:31788332). The variant was identified in dbSNP (ID: rs534723946) and ClinVar (classified as uncertain significance by the Inherited Neuropathy Consortium and Genomic Research Center, Shahid Beheshti University of Medical Sciences, and as probable-pathogenic by the Northcott Neuroscience Laboratory, ANZAC Research Institute). The variant was identified in control databases in 138 of 282726 chromosomes at a frequency of 0.0004881 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 108 of 30616 chromosomes (freq: 0.003528), Other in 5 of 7218 chromosomes (freq: 0.000693), East Asian in 12 of 19954 chromosomes (freq: 0.000601), African in 2 of 24966 chromosomes (freq: 0.00008), European (non-Finnish) in 9 of 129050 chromosomes (freq: 0.00007) and Latino in 2 of 35438 chromosomes (freq: 0.000056), but was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Arg502 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely pathogenic, no assertion criteria provided | literature only | Northcott Neuroscience Laboratory, ANZAC Research Institute | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2019 | See Variant Classification Assertion Criteria. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 17, 2020 | - - |
Amyotrophic lateral sclerosis type 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The amino acid Arg at position 502 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Likely_pathogenic, however details are not available for independent assessment. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg502Trp in SETX is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at