rs121912438
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000454.5(SOD1):c.281G>C(p.Gly94Ala) variant causes a missense change. 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. G94R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SOD1
NM_000454.5 missense
NM_000454.5 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 5.97
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 12 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000454.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr21-31667298-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
?
Variant 21-31667299-G-C is Pathogenic according to our data. Variant chr21-31667299-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14760.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.281G>C | p.Gly94Ala | missense_variant | 4/5 | ENST00000270142.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.281G>C | p.Gly94Ala | missense_variant | 4/5 | 1 | NM_000454.5 | P1 | |
SOD1 | ENST00000389995.4 | c.224G>C | p.Gly75Ala | missense_variant | 4/5 | 3 | |||
SOD1 | ENST00000470944.1 | n.1209G>C | non_coding_transcript_exon_variant | 4/5 | 2 | ||||
SOD1 | ENST00000476106.5 | n.544G>C | non_coding_transcript_exon_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251484Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135922
GnomAD3 exomes
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2
AN:
251484
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0
AN XY:
135922
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GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 2022 | This missense change has been observed in individual(s) with familial amyotrophic lateral sclerosis (PMID: 8446170, 15258228, 23541756). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly94 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9029070, 18273717, 21120636, 24325798). 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: 8650157, 12482932, 15050437, 15208263, 19483195, 33381076). 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: 14760). This variant is also known as p.Gly93Ala or G93A. This variant is present in population databases (rs121912438, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 94 of the SOD1 protein (p.Gly94Ala). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 25, 1997 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of ubiquitination at K92 (P = 0.077);.;
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