rs1382990384
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_015046.7(SETX):c.7413A>T(p.Arg2471Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SETX
NM_015046.7 missense
NM_015046.7 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: -0.829
Genes affected
SETX (HGNC:445): (senataxin) This gene encodes a protein named for its homology to the Sen1p protein of fungi which has RNA helicase activity encoded by a domain at the C-terminal end of the protein. The protein encoded by this gene contains a DNA/RNA helicase domain at its C-terminal end which suggests that it may be involved in both DNA and RNA processing. Mutations in this gene have been associated with ataxia-ocular apraxia-2 (AOA2) and an autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS4). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27787235).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SETX | NM_015046.7 | c.7413A>T | p.Arg2471Ser | missense_variant | 26/26 | ENST00000224140.6 | NP_055861.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SETX | ENST00000224140.6 | c.7413A>T | p.Arg2471Ser | missense_variant | 26/26 | 1 | NM_015046.7 | ENSP00000224140.5 | ||
SETX | ENST00000436441.5 | c.2226A>T | p.Arg742Ser | missense_variant | 17/17 | 5 | ENSP00000409143.1 | |||
SETX | ENST00000477049.1 | n.563A>T | non_coding_transcript_exon_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727226
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2020 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SETX-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 2471 of the SETX protein (p.Arg2471Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 31, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;D
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
0.46
MutPred
0.41
.;Loss of MoRF binding (P = 0.02);
MVP
MPC
0.44
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at