rs80265967

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate

The NM_000454.5(SOD1):​c.272A>T​(p.Asp91Val) 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SOD1
NM_000454.5 missense

Scores

7
5
7

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.308
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1
Transcript NM_000454.5 (SOD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 8 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 chr21-31667290-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14766.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=6, Uncertain_significance=4}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
Variant 21-31667290-A-T is Pathogenic according to our data. Variant chr21-31667290-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1802147.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOD1NM_000454.5 linkuse as main transcriptc.272A>T p.Asp91Val missense_variant 4/5 ENST00000270142.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOD1ENST00000270142.11 linkuse as main transcriptc.272A>T p.Asp91Val missense_variant 4/51 NM_000454.5 P1
ENST00000609934.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenDec 07, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.26
CADD
Benign
15
DANN
Benign
0.89
DEOGEN2
Pathogenic
0.98
D;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.19
N
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.4
D
MutationAssessor
Pathogenic
3.5
M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.011
D;D
Sift4G
Uncertain
0.044
D;T
Polyphen
0.0060
B;.
Vest4
0.72
MutPred
0.77
Loss of disorder (P = 0.0206);.;
MVP
0.86
MPC
1.7
ClinPred
0.28
T
GERP RS
-5.9
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.1
Varity_R
0.59
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80265967; hg19: chr21-33039603; API