rs1799895

Positions:

• chr4-24800212-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003102.4(SOD3):​c.691C>G​(p.Arg231Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,431,336 control chromosomes in the GnomAD database, including 312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 32)
  • Exomes 𝑓: 0.016 (292 hom.)
• Consequence: SOD3 NM_003102.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 B:1
• Conservation: PhyloP100: 1.39

Genes affected

SOD3 (HGNC:11181): (superoxide dismutase 3) This gene encodes a member of the superoxide dismutase (SOD) protein family. SODs are antioxidant enzymes that catalyze the conversion of superoxide radicals into hydrogen peroxide and oxygen, which may protect the brain, lungs, and other tissues from oxidative stress. Proteolytic processing of the encoded protein results in the formation of two distinct homotetramers that differ in their ability to interact with the extracellular matrix (ECM). Homotetramers consisting of the intact protein, or type C subunit, exhibit high affinity for heparin and are anchored to the ECM. Homotetramers consisting of a proteolytically cleaved form of the protein, or type A subunit, exhibit low affinity for heparin and do not interact with the ECM. A mutation in this gene may be associated with increased heart disease risk. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052476227).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOD3	NM_003102.4	c.691C>G	p.Arg231Gly	missense_variant	2/2	ENST00000382120.4	NP_003093.2
SOD3	XR_427488.2	n.786C>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOD3	ENST00000382120.4	c.691C>G	p.Arg231Gly	missense_variant	2/2	1	NM_003102.4	ENSP00000371554	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1931 AN: 152106 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0221

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0225 AC: 1116 AN: 49574 Hom.: 20 AF XY: 0.0242 AC XY: 691 AN XY: 28594

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0212

Gnomad SAS exome AF: 0.0534

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0157 AC: 20136 AN: 1279118 Hom.: 292 Cov.: 35 AF XY: 0.0168 AC XY: 10556 AN XY: 628084

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.0402

Gnomad4 SAS exome AF: 0.0567

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0127 AC: 1940 AN: 152218 Hom.: 20 Cov.: 32 AF XY: 0.0140 AC XY: 1043 AN XY: 74420

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.0220

Gnomad4 SAS AF: 0.0592

Gnomad4 FIN AF: 0.0147

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0112 Hom.: 0

Bravo AF: 0.0109

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0138 AC: 53

ExAC AF: 0.0212 AC: 411

Asia WGS AF: 0.0470 AC: 165 AN: 3470

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Superoxide dismutase, elevated extracellular Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 06, 2004

- -

SOD3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.038	A
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.017	D
Polyphen		0.067	B
Vest4		0.12
MPC		1.9
ClinPred		0.046	T
GERP RS		1.2
Varity_R		0.30
gMVP		0.54

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: rs1799895; hg19: chr4-24801834; COSMIC: COSV66125784; COSMIC: COSV66125784;