4-24799604-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_003102.4(SOD3):c.83A>G(p.Asn28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,604,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: SOD3 NM_003102.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.117

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043355525).
• BP6: Variant 4-24799604-A-G is Benign according to our data. Variant chr4-24799604-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3037717.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD3	NM_003102.4	c.83A>G	p.Asn28Ser	missense_variant	2/2	ENST00000382120.4
SOD3	XR_427488.2	n.178A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD3	ENST00000382120.4	c.83A>G	p.Asn28Ser	missense_variant	2/2	1	NM_003102.4	P1
SOD3	ENST00000598411.1	c.83A>G	p.Asn28Ser	missense_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000299 AC: 69 AN: 231028 Hom.: 1 AF XY: 0.000260 AC XY: 33 AN XY: 126990

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000683

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000159 AC: 231 AN: 1452328 Hom.: 2 Cov.: 31 AF XY: 0.000159 AC XY: 115 AN XY: 722476

Gnomad4 AFR exome AF: 0.00536

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.000465

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74436

Gnomad4 AFR AF: 0.00529

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.00178

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000322 AC: 39

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SOD3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2022

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	0.051
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.12
Dann	Benign	0.19
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0043	T;T
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.14	T;T
Polyphen		0.0	.;B
Vest4		0.030
MVP		0.67
MPC		0.74
ClinPred		0.0017	T
GERP RS		0.78
Varity_R		0.022
gMVP		0.48

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: rs144089452; hg19: chr4-24801226;