chr11-89340134-A-T

Variant names:

• chr11-89340134-A-T
• rs745316929
• NM_016931.5:c.1375T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016931.5(NOX4):​c.1375T>A​(p.Phe459Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,218 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F459L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.66
• Publications: 0 publications found

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]

ACMG classification

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, 0.871

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOX4	NM_016931.5	MANE Select	c.1375T>A	p.Phe459Ile	missense	Exon 15 of 18	NP_058627.2	Q9NPH5-1
	NOX4	NM_001291927.1		c.1438T>A	p.Phe480Ile	missense	Exon 15 of 18	NP_001278856.1	Q9NPH5
	NOX4	NM_001143837.2		c.1303T>A	p.Phe435Ile	missense	Exon 18 of 21	NP_001137309.2	Q9NPH5-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOX4	ENST00000263317.9	TSL:1 MANE Select	c.1375T>A	p.Phe459Ile	missense	Exon 15 of 18	ENSP00000263317.4	Q9NPH5-1
	NOX4	ENST00000534731.5	TSL:1	c.1255T>A	p.Phe419Ile	missense	Exon 14 of 17	ENSP00000436892.1	Q9NPH5-6
	NOX4	ENST00000525196.5	TSL:1	c.667T>A	p.Phe223Ile	missense	Exon 9 of 12	ENSP00000436716.1	E9PI95

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000445 AC: 1 AN: 224478 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000486 AC: 7 AN: 1439380 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 716090

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.0000513 AC: 2 AN: 38974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 38488

South Asian (SAS) AF: 0.00 AC: 0 AN: 82254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1104626

Other (OTH) AF: 0.00 AC: 0 AN: 59344

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.55		Gain of MoRF binding (P = 0.1365)
MVP		0.98
MPC		0.21
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.80
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs745316929; hg19: chr11-89073302;