rs121434380
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5
The NM_015046.7(SETX):c.5929C>T(p.Leu1977Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,004 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1977L) has been classified as Likely benign.
Frequency
Consequence
NM_015046.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETX | NM_015046.7 | c.5929C>T | p.Leu1977Phe | missense_variant | 14/26 | ENST00000224140.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETX | ENST00000224140.6 | c.5929C>T | p.Leu1977Phe | missense_variant | 14/26 | 1 | NM_015046.7 | P1 | |
SETX | ENST00000436441.5 | c.655C>T | p.Leu219Phe | missense_variant | 4/17 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251446Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727230
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 19, 2019 | The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24760770, 25725227, 25116135, 23129421, 19697368, 33333218, 24393486, 19696032, 17159128, 26147798) - |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 12, 2006 | - - |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1977 of the SETX protein (p.Leu1977Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of spinocerebellar ataxia (PMID: 17159128, 19696032). ClinVar contains an entry for this variant (Variation ID: 2295). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SETX protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SETX function (PMID: 25116135). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at