Genetic Variant SOD3:p.Ala3Ala (chr4-24799530-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003102.4(SOD3):c.9G>C(p.Ala3Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,599,408 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 119 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 118 hom. )

Consequence

SOD3
NM_003102.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0970

Publications

2 publications found

Variant links:

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]

SOD3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 4-24799530-G-C is Benign according to our data. Variant chr4-24799530-G-C is described in ClinVar as [Benign]. Clinvar id is 775951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.097 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD3	NM_003102.4 link	c.9G>C	p.Ala3Ala	synonymous_variant	Exon 2 of 2	ENST00000382120.4	NP_003093.2
SOD3	XR_427488.2 link	n.104G>C		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD3	ENST00000382120.4 link	c.9G>C	p.Ala3Ala	synonymous_variant	Exon 2 of 2	1	NM_003102.4	ENSP00000371554.3		P08294
SOD3	ENST00000598411.1 link	c.9G>C	p.Ala3Ala	synonymous_variant	Exon 3 of 3	5		ENSP00000472134.1		M0R1V4

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

3418

AN:

152190

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.00586

AC:

1319

AN:

224946

AF XY:

0.00466

show subpopulations

Gnomad AFR exome

AF:

0.0758

Gnomad AMR exome

AF:

0.00542

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.000515

Gnomad FIN exome

AF:

0.0000792

Gnomad NFE exome

AF:

0.000566

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00266

AC:

3850

AN:

1447100

Hom.:

118

Cov.:

AF XY:

0.00241

AC XY:

1738

AN XY:

720288

show subpopulations

African (AFR)

AF:

0.0770

AC:

2573

AN:

33432

American (AMR)

AF:

0.00636

AC:

283

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26052

East Asian (EAS)

AF:

0.000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.000245

AC:

AN:

85710

European-Finnish (FIN)

AF:

0.0000738

AC:

AN:

40674

Middle Eastern (MID)

AF:

0.00886

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000460

AC:

511

AN:

1111170

Other (OTH)

AF:

0.00660

AC:

397

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

206

412

618

824

1030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0224

AC:

3412

AN:

152308

Hom.:

119

Cov.:

AF XY:

0.0216

AC XY:

1607

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0746

AC:

3101

AN:

41566

American (AMR)

AF:

0.0135

AC:

206

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5162

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68020

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

166

331

497

662

828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.0257

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.097

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-24799530-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over