rs121912444
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000454.5(SOD1):c.13G>A(p.Ala5Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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. A5S) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SOD1
NM_000454.5 missense
NM_000454.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.53
Genes affected
SOD1 (HGNC:11179): (superoxide dismutase 1) The protein encoded by this gene binds copper and zinc ions and is one of two isozymes responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic protein, acting as a homodimer to convert naturally-occuring but harmful superoxide radicals to molecular oxygen and hydrogen peroxide. The other isozyme is a mitochondrial protein. In addition, this protein contains an antimicrobial peptide that displays antibacterial, antifungal, and anti-MRSA activity against E. coli, E. faecalis, S. aureus, S. aureus MRSA LPV+, S. agalactiae, and yeast C. krusei. Mutations in this gene have been implicated as causes of familial amyotrophic lateral sclerosis. Rare transcript variants have been reported for this gene. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000454.5
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr21-31659782-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 873321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
?
Variant 21-31659782-G-A is Pathogenic according to our data. Variant chr21-31659782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.13G>A | p.Ala5Thr | missense_variant | 1/5 | ENST00000270142.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.13G>A | p.Ala5Thr | missense_variant | 1/5 | 1 | NM_000454.5 | P1 | |
SOD1 | ENST00000389995.4 | c.13G>A | p.Ala5Thr | missense_variant, splice_region_variant | 1/5 | 3 | |||
SOD1 | ENST00000470944.1 | n.74G>A | non_coding_transcript_exon_variant | 1/5 | 2 | ||||
SOD1 | ENST00000476106.5 | n.90G>A | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250486Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135690
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461522Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727088
GnomAD4 exome
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GnomAD4 genome ? Cov.: 33
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Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 23, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951249, 8351519, 19176896, 19618436). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOD1 function (PMID: 8179602, 17543992, 21257910, 23280792, 26362407). 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 SOD1 protein function. ClinVar contains an entry for this variant (Variation ID: 14765). This variant is also known as p.Ala4Thr. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 8179602, 12792143, 17543992, 22292843). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the SOD1 protein (p.Ala5Thr). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 11, 1994 | - - |
Pathogenic, criteria provided, single submitter | research | Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University | Mar 31, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 09, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N
REVEL
Pathogenic
Sift
Pathogenic
D;T
Sift4G
Pathogenic
D;T
Polyphen
D;.
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at