rs121912456
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000454.5(SOD1):c.37G>C(p.Gly13Arg) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G13G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
SOD1
NM_000454.5 missense
NM_000454.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 3.03
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 10 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000454.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
?
Variant 21-31659806-G-C is Pathogenic according to our data. Variant chr21-31659806-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14780.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.37G>C | p.Gly13Arg | missense_variant | 1/5 | ENST00000270142.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.37G>C | p.Gly13Arg | missense_variant | 1/5 | 1 | NM_000454.5 | P1 | |
SOD1 | ENST00000389995.4 | c.15+22G>C | intron_variant | 3 | |||||
SOD1 | ENST00000470944.1 | n.98G>C | non_coding_transcript_exon_variant | 1/5 | 2 | ||||
SOD1 | ENST00000476106.5 | n.114G>C | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This variant has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 28035186, 11369193, 14506936). ClinVar contains an entry for this variant (Variation ID: 14780). This variant is also known as p.Gly12Arg. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 13 of the SOD1 protein (p.Gly13Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2001 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of solvent accessibility (P = 0.019);
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