NM_016931.5:c.748C>A

Variant names:

• chr11-89402424-G-T
• rs201676793
• NM_016931.5:c.748C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016931.5(NOX4):​c.748C>A​(p.Pro250Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,222 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.787
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013273299).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.748C>A	p.Pro250Thr	missense	Exon 9 of 18	NP_058627.2	Q9NPH5-1
	NOX4	NM_001291927.1		c.811C>A	p.Pro271Thr	missense	Exon 9 of 18	NP_001278856.1	Q9NPH5
	NOX4	NM_001143837.2		c.676C>A	p.Pro226Thr	missense	Exon 12 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.748C>A	p.Pro250Thr	missense	Exon 9 of 18	ENSP00000263317.4	Q9NPH5-1
	NOX4	ENST00000534731.5	TSL:1	c.748C>A	p.Pro250Thr	missense	Exon 9 of 17	ENSP00000436892.1	Q9NPH5-6
	NOX4	ENST00000525196.5	TSL:1	c.629+19478C>A		intron	N/A	ENSP00000436716.1	E9PI95

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000160 AC: 40 AN: 250262 AF XY: 0.000244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 233 AN: 1461066 Hom.: 2 Cov.: 31 AF XY: 0.000213 AC XY: 155 AN XY: 726822

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.0000896 AC: 4 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00111 AC: 96 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111580

Other (OTH) AF: 0.000149 AC: 9 AN: 60362

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41516

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000529 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

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	Benign	0.060
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	12
DANN	Benign	0.56
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.79
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.14
Sift	Benign	0.094	T
Sift4G	Uncertain	0.047	D
Polyphen		0.026	B
Vest4		0.13
MVP		0.83
MPC		0.052
ClinPred		0.023	T
GERP RS		-3.2
Varity_R		0.038
gMVP		0.42
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs201676793; hg19: chr11-89135592; COSMIC: COSV106387190;