rs201676793

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-89402424-G-A
• chr11-89402424-G-C
• chr11-89402424-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016931.5(NOX4):​c.748C>T​(p.Pro250Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. P250T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052849293).

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>T	p.Pro250Ser	missense	Exon 9 of 18	NP_058627.2	Q9NPH5-1
	NOX4	NM_001291927.1		c.811C>T	p.Pro271Ser	missense	Exon 9 of 18	NP_001278856.1	Q9NPH5
	NOX4	NM_001143837.2		c.676C>T	p.Pro226Ser	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>T	p.Pro250Ser	missense	Exon 9 of 18	ENSP00000263317.4	Q9NPH5-1
	NOX4	ENST00000534731.5	TSL:1	c.748C>T	p.Pro250Ser	missense	Exon 9 of 17	ENSP00000436892.1	Q9NPH5-6
	NOX4	ENST00000525196.5	TSL:1	c.629+19478C>T		intron	N/A	ENSP00000436716.1	E9PI95

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461066 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726822

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000270 AC: 3 AN: 1111580

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000529 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.48
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.79
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.17
Sift	Benign	0.42	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.35		Loss of catalytic residue at P250 (P = 0.0226)
MVP		0.79
MPC		0.048
ClinPred		0.034	T
GERP RS		-3.2
Varity_R		0.026
gMVP		0.38
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: COSV104372932;