rs369650195

Variant names:

• chr11-89400316-G-A
• rs369650195
• NM_016931.5:c.910C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-89400316-G-A
• chr11-89400316-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_016931.5(NOX4):​c.910C>T​(p.Arg304Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,612,626 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: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18
• Publications: 2 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

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.910C>T	p.Arg304Trp	missense	Exon 10 of 18	NP_058627.2	Q9NPH5-1
	NOX4	NM_001291927.1		c.973C>T	p.Arg325Trp	missense	Exon 10 of 18	NP_001278856.1	Q9NPH5
	NOX4	NM_001143837.2		c.838C>T	p.Arg280Trp	missense	Exon 13 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.910C>T	p.Arg304Trp	missense	Exon 10 of 18	ENSP00000263317.4	Q9NPH5-1
	NOX4	ENST00000534731.5	TSL:1	c.910C>T	p.Arg304Trp	missense	Exon 10 of 17	ENSP00000436892.1	Q9NPH5-6
	NOX4	ENST00000525196.5	TSL:1	c.629+21586C>T		intron	N/A	ENSP00000436716.1	E9PI95

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151966 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: 0.000387

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000560 AC: 14 AN: 250080 AF XY: 0.0000518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000993 AC: 145 AN: 1460660 Hom.: 0 Cov.: 33 AF XY: 0.000106 AC XY: 77 AN XY: 726618

African (AFR) AF: 0.0000598 AC: 2 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26096

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39610

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111262

Other (OTH) AF: 0.0000663 AC: 4 AN: 60320

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74192

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

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	0.16
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.66		Gain of ubiquitination at K307 (P = 0.048)
MVP		0.99
MPC		0.054
ClinPred		0.92	D
GERP RS		2.1
Varity_R		0.66
gMVP		0.71
Mutation Taster		=54/46	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: rs369650195; hg19: chr11-89133484;