Genetic Variant NM_016931.5:c.862T>C (chr11-89400364-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016931.5(NOX4):c.862T>C(p.Ser288Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000049 in 1,429,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S288A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

NOX4
NM_016931.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.73

Publications

0 publications found

Variant links:

Genes affected

NOX4 (HGNC:7891): (NADPH oxidase 4) This gene encodes a member of the NOX-family of enzymes that functions as the catalytic subunit the NADPH oxidase complex. The encoded protein is localized to non-phagocytic cells where it acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in numerous biological functions including signal transduction, cell differentiation and tumor cell growth. A pseudogene has been identified on the other arm of chromosome 11. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]

NOX4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016931.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOX4	NM_016931.5	MANE Select	c.862T>C	p.Ser288Pro	missense	Exon 10 of 18	NP_058627.2	Q9NPH5-1
NOX4	NM_001291927.1		c.925T>C	p.Ser309Pro	missense	Exon 10 of 18	NP_001278856.1	Q9NPH5
NOX4	NM_001143837.2		c.790T>C	p.Ser264Pro	missense	Exon 13 of 21	NP_001137309.2	Q9NPH5-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOX4	ENST00000263317.9	TSL:1 MANE Select	c.862T>C	p.Ser288Pro	missense	Exon 10 of 18	ENSP00000263317.4	Q9NPH5-1
NOX4	ENST00000534731.5	TSL:1	c.862T>C	p.Ser288Pro	missense	Exon 10 of 17	ENSP00000436892.1	Q9NPH5-6
NOX4	ENST00000525196.5	TSL:1	c.629+21538T>C		intron	N/A	ENSP00000436716.1	E9PI95

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000490

AC:

AN:

1429300

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32298

American (AMR)

AF:

0.00

AC:

AN:

38932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24740

East Asian (EAS)

AF:

0.00

AC:

AN:

39160

South Asian (SAS)

AF:

0.00

AC:

AN:

78506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.00000637

AC:

AN:

1098572

Other (OTH)

AF:

0.00

AC:

AN:

58992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.3

PhyloP100

6.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.88

Sift

Benign

0.038

Sift4G

Uncertain

0.019

Polyphen

0.98

Vest4

0.82

MutPred

0.75

Loss of sheet (P = 0.0817)

MVP

0.98

MPC

0.30

ClinPred

0.95

GERP RS

5.2

Varity_R

0.64

gMVP

0.79

Mutation Taster

=23/77

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over