Genetic Variant NOXA1:p.Leu125Pro (chr9-137428886-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001256067.2(NOXA1):c.374T>C(p.Leu125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NOXA1
NM_001256067.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.643

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2 link	c.374T>C	p.Leu125Pro	missense_variant	Exon 4 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.374T>C	p.Leu125Pro	missense_variant	Exon 4 of 14		NM_001256067.2	ENSP00000507846.1		Q86UR1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32668

American (AMR)

AF:

0.00

AC:

AN:

40512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25494

East Asian (EAS)

AF:

0.00

AC:

AN:

37772

South Asian (SAS)

AF:

0.00

AC:

AN:

81844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097394

Other (OTH)

AF:

0.00

AC:

AN:

59152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000660

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.374T>C (p.L125P) alteration is located in exon 4 (coding exon 4) of the NOXA1 gene. This alteration results from a T to C substitution at nucleotide position 374, causing the leucine (L) at amino acid position 125 to be replaced by a proline (P). 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

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.096

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

0.64

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.81

Loss of stability (P = 0.0289);Loss of stability (P = 0.0289);

MVP

0.58

MPC

0.54

ClinPred

0.93

GERP RS

1.8

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

gMVP

0.91

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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chr9-137428886-T-C

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