rs29001584
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_015046.7(SETX):c.1166T>C(p.Leu389Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L389F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015046.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETX | NM_015046.7 | c.1166T>C | p.Leu389Ser | missense_variant | 10/26 | ENST00000224140.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETX | ENST00000224140.6 | c.1166T>C | p.Leu389Ser | missense_variant | 10/26 | 1 | NM_015046.7 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 30, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2023 | Published functional studies demonstrate increased promoter methylation and decreased gene transcription, by reducing R-loops and BAMBI expression, while increasing TGF-B signaling (Grunseich et al., 2018).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30528841, 32997296, 24244371, 24105744, 29395064, 29725819, 9497266, 10430837, 23129421, 22088787, 29916023, 28413711, 27796045, 31957062, 15106121, 21438761) - |
Amyotrophic lateral sclerosis type 4 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2004 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 06, 2022 | ClinVar contains an entry for this variant (Variation ID: 2289). For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SETX function (PMID: 21576111, 24105744, 24244371). 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 expected to disrupt SETX protein function. This missense change has been observed in individuals with autosomal dominant juvenile amyotrophic lateral sclerosis (PMID: 15106121, 21438761, 22088787). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 389 of the SETX protein (p.Leu389Ser). - |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Distal spinal muscular atrophy Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at