Genetic Variant NM_001256067.2:c.547G>A (chr9-137429318-G-A) – 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_001256067.2(NOXA1):c.547G>A(p.Val183Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,426,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NOXA1
NM_001256067.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.560

Publications

0 publications found

Variant links:

Genes affected

NOXA1 (HGNC:10668): (NADPH oxidase activator 1) This gene encodes a protein which activates NADPH oxidases, enzymes which catalyze a reaction generating reactive oxygen species. The encoded protein contains four N-terminal tetratricopeptide domains and a C-terminal Src homology 3 domain. Interaction between the encoded protein and proteins in the oxidase regulatory complex occur via the tetratricopeptide domains. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

NOXA1 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=0.2240763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2 link	c.547G>A	p.Val183Ile	missense_variant	Exon 5 of 14	ENST00000683555.1	NP_001242996.1	Q86UR1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOXA1	ENST00000683555.1 link	c.547G>A	p.Val183Ile	missense_variant	Exon 5 of 14		NM_001256067.2	ENSP00000507846.1		Q86UR1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000521

AC:

AN:

191782

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1426528

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.00

AC:

AN:

38732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

38264

South Asian (SAS)

AF:

0.00

AC:

AN:

81298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1095716

Other (OTH)

AF:

0.00

AC:

AN:

59080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.547G>A (p.V183I) alteration is located in exon 5 (coding exon 5) of the NOXA1 gene. This alteration results from a G to A substitution at nucleotide position 547, causing the valine (V) at amino acid position 183 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.67

M_CAP

Benign

0.057

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

PhyloP100

0.56

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.050

REVEL

Benign

0.15

Sift

Benign

0.077

Sift4G

Benign

0.11

Polyphen

0.96

Vest4

0.17

MutPred

0.29

Gain of helix (P = 0.0496);

MVP

0.52

MPC

0.40

ClinPred

0.28

GERP RS

2.2

gMVP

0.17

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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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NM_001256067.2:c.547G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over