4-24799792-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_003102.4(SOD3):c.271G>A(p.Ala91Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,587,406 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: SOD3 NM_003102.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.668

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008452237).
• BP6: Variant 4-24799792-G-A is Benign according to our data. Variant chr4-24799792-G-A is described in ClinVar as [Benign]. Clinvar id is 708784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD3	NM_003102.4	c.271G>A	p.Ala91Thr	missense_variant	2/2	ENST00000382120.4
SOD3	XR_427488.2	n.366G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD3	ENST00000382120.4	c.271G>A	p.Ala91Thr	missense_variant	2/2	1	NM_003102.4	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000665 AC: 131 AN: 196998 Hom.: 0 AF XY: 0.000536 AC XY: 59 AN XY: 110026

Gnomad AFR exome AF: 0.00782

Gnomad AMR exome AF: 0.000857

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: 0.000207

Gnomad OTH exome AF: 0.000585

GnomAD4 exome AF: 0.000378 AC: 543 AN: 1435152 Hom.: 0 Cov.: 35 AF XY: 0.000370 AC XY: 264 AN XY: 713280

Gnomad4 AFR exome AF: 0.00859

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000754

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74426

Gnomad4 AFR AF: 0.00743

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.00260

ESP6500AA AF: 0.00686 AC: 25

ESP6500EA AF: 0.000527 AC: 4

ExAC AF: 0.000606 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2018

- -

SOD3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 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	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.021	D
Polyphen		0.39	B
Vest4		0.086
MVP		0.90
MPC		1.2
ClinPred		0.049	T
GERP RS		3.2
Varity_R		0.35
gMVP		0.62

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: rs17879876; hg19: chr4-24801414; COSMIC: COSV66125903; COSMIC: COSV66125903;