rs2536512

Positions:

• chr4-24799693-G-A
• chr4-24799693-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003102.4(SOD3):​c.172G>A​(p.Ala58Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,578,062 control chromosomes in the GnomAD database, including 302,909 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (22364 hom., cov: 33)
  • Exomes 𝑓: 0.62 (280545 hom.)
• Consequence: SOD3 NM_003102.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.06

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6705037E-6).
• BP6: Variant 4-24799693-G-A is Benign according to our data. Variant chr4-24799693-G-A is described in ClinVar as [Benign]. Clinvar id is 3060834.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOD3	NM_003102.4	c.172G>A	p.Ala58Thr	missense_variant	2/2	ENST00000382120.4	NP_003093.2
SOD3	XR_427488.2	n.267G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOD3	ENST00000382120.4	c.172G>A	p.Ala58Thr	missense_variant	2/2	1	NM_003102.4	ENSP00000371554	P1
SOD3	ENST00000598411.1			downstream_gene_variant		5		ENSP00000472134

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76267 AN: 151936 Hom.: 22372 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.520

GnomAD3 exomes AF: 0.552 AC: 100699 AN: 182560 Hom.: 29607 AF XY: 0.565 AC XY: 57280 AN XY: 101358

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.329

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.618 AC: 881954 AN: 1426010 Hom.: 280545 Cov.: 69 AF XY: 0.617 AC XY: 436815 AN XY: 707466

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.515

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.655

Gnomad4 OTH exome AF: 0.587

GnomAD4 genome AF: 0.502 AC: 76261 AN: 152052 Hom.: 22364 Cov.: 33 AF XY: 0.504 AC XY: 37452 AN XY: 74332

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.753

Gnomad4 NFE AF: 0.653

Gnomad4 OTH AF: 0.518

Alfa AF: 0.613 Hom.: 14262

Bravo AF: 0.468

TwinsUK AF: 0.665 AC: 2466

ALSPAC AF: 0.666 AC: 2568

ESP6500AA AF: 0.257 AC: 1082

ESP6500EA AF: 0.662 AC: 5556

ExAC AF: 0.519 AC: 58693

Asia WGS AF: 0.408 AC: 1419 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SOD3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as 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	0.069
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.054
DANN	Benign	0.89
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.011
Sift	Benign	0.70	T
Sift4G	Benign	0.78	T
Polyphen		0.19	B
Vest4		0.011
MPC		0.91
ClinPred		0.0032	T
GERP RS		-1.3
Varity_R		0.066
gMVP		0.66

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: rs2536512; hg19: chr4-24801315; COSMIC: COSV66125434; COSMIC: COSV66125434;