Genetic Variant SOD3:p.Asp56His (chr4-24799687-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003102.4(SOD3):c.166G>C(p.Asp56His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D56N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SOD3
NM_003102.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.37

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20238873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD3	NM_003102.4 link	c.166G>C	p.Asp56His	missense_variant	Exon 2 of 2	ENST00000382120.4	NP_003093.2
SOD3	XR_427488.2 link	n.261G>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.166G>C	p.Asp56His	missense_variant	Exon 2 of 2	1	NM_003102.4	ENSP00000371554.3		P08294
SOD3	ENST00000598411.1 link	c.*4G>C		downstream_gene_variant		5		ENSP00000472134.1		M0R1V4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435058

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32922

American (AMR)

AF:

0.00

AC:

AN:

41830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25762

East Asian (EAS)

AF:

0.00

AC:

AN:

38144

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44734

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102902

Other (OTH)

AF:

0.00

AC:

AN:

59508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.069

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.5

PhyloP100

2.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.30

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.034

Polyphen

0.81

Vest4

0.11

MutPred

0.29

Gain of helix (P = 0.132);

MVP

0.73

MPC

1.3

ClinPred

0.32

GERP RS

2.9

Varity_R

0.28

gMVP

0.80

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over