rs121912458

Positions:

• chr21-31667260-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000454.5(SOD1):​c.242A>G​(p.His81Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H81A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.73

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a mutagenesis_site Loss of zinc binding and enhanced tendency to form aggregates; when associated with A-84. (size 0) in uniprot entity SODC_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-31667260-A-G is Pathogenic according to our data. Variant chr21-31667260-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14782.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOD1	NM_000454.5	c.242A>G	p.His81Arg	missense_variant, splice_region_variant	4/5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.242A>G	p.His81Arg	missense_variant, splice_region_variant	4/5	1	NM_000454.5	ENSP00000270142	P1
	ENST00000609934.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251352 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2020	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SOD1 protein function (PMID: 16945901, 19483195, 20515040, 23280792). This variant has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 12402272). In at least one individual the variant was observed to be de novo. This variant is also known as His80Arg. ClinVar contains an entry for this variant (Variation ID: 14782). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 81 of the SOD1 protein (p.His81Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.98		Gain of methylation at K76 (P = 0.0495);.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.98
gMVP		0.99

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

Other links and lift over

dbSNP: rs121912458; hg19: chr21-33039573; COSMIC: COSV99532295; COSMIC: COSV99532295;