21-31659803-G-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate
The NM_000454.5(SOD1):c.34G>T(p.Asp12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SOD1
NM_000454.5 missense
NM_000454.5 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 2.20
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 Likely_pathogenic. Variant got 7 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, 0.808
PP5
Variant 21-31659803-G-T is Pathogenic according to our data. Variant chr21-31659803-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2690932.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.34G>T | p.Asp12Tyr | missense_variant | 1/5 | ENST00000270142.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.34G>T | p.Asp12Tyr | missense_variant | 1/5 | 1 | NM_000454.5 | P1 | |
SOD1 | ENST00000389995.4 | c.15+19G>T | intron_variant | 3 | |||||
SOD1 | ENST00000470944.1 | n.95G>T | non_coding_transcript_exon_variant | 1/5 | 2 | ||||
SOD1 | ENST00000476106.5 | n.111G>T | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135670
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461510Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727088
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74400
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital | Jan 29, 2024 | This variant was detected in homozygous state in a male patient with a clinical diagnosis of ALS1 in his early 40s. Patient presented with rapidly progressive limb weakness over 1.5 years. The c.34G>T variant (p.(Asp12Tyr), also known as D11Y) has been reported in multiple heterozygous individuals with ALS1 in Italian population (PMID: 20740631, 21839474, 32987860, 35328090). It was suggested this variant has a founder effect in Italian population with specific phenotype and incomplete penetrance as a dominant trait (PMID: 22292847, 38112783). Described patients with heterozygous SOD1 c.34G>T variant showed slow progression with distal limb involvement, and predominant lower motor neuron signs (PMID: 32250500). It is found in control population at low frequency (rs762628133, gnomAD 0.0003%). In silico analysis suggests this variant to be damaging (REVEL: 0.65). The variant is in the critical superoxide dismutase copper/zinc binding domain (IPR001424). The current evidence allows a classification of the variant as “likely pathogenic” (ACMG criteria: PM1, PM2_supporting, PM3_supporting, PP1_moderate, PP3). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of MoRF binding (P = 0.0708);
MVP
MPC
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