NM_000454.5:c.10A>G

Variant names:

• chr21-31659779-A-G
• rs1568807297
• NM_000454.5:c.10A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000454.5(SOD1):​c.10A>G​(p.Lys4Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,554 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.26
• Publications: 1 publications found

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]

SOD1-DT (HGNC:55683): (SOD1 divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 17 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, 7 uncertain in NM_000454.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 96 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.83817 (below the threshold of 3.09). Trascript score misZ: 1.2198 (below the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 1, amyotrophic lateral sclerosis, spastic tetraplegia and axial hypotonia, progressive.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 21-31659779-A-G is Pathogenic according to our data. Variant chr21-31659779-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2138372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000454.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	NM_000454.5	MANE Select	c.10A>G	p.Lys4Glu	missense	Exon 1 of 5	NP_000445.1	P00441
	SOD1-DT	NR_187558.1		n.246T>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	ENST00000270142.11	TSL:1 MANE Select	c.10A>G	p.Lys4Glu	missense	Exon 1 of 5	ENSP00000270142.7	P00441
	SOD1	ENST00000877332.1		c.10A>G	p.Lys4Glu	missense	Exon 1 of 5	ENSP00000547391.1
	SOD1	ENST00000877328.1		c.10A>G	p.Lys4Glu	missense	Exon 1 of 4	ENSP00000547387.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461554 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Amyotrophic lateral sclerosis type 1 (1)
1	-	-	not provided (1)
1	-	-	SOD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.017	D
Polyphen		0.82	P
Vest4		0.54
MutPred		0.83		Loss of ubiquitination at K4 (P = 0.0161)
MVP		0.99
MPC		1.9
ClinPred		0.98	D
GERP RS		3.9
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.96
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs1568807297; hg19: chr21-33032092;