rs3749930

Positions:

• chr6-155440112-G-C
• chr6-155440112-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015718.3(NOX3):​c.512C>G​(p.Thr171Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T171K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOX3 NM_015718.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15

Genes affected

NOX3 (HGNC:7890): (NADPH oxidase 3) This gene encodes a member of the NOX family of NADPH oxidases. These enzymes have the capacity to generate superoxide and other reactive oxygen species (ROS) and transport electrons across the plasma membrane. The ROS generated by family members have been implicated in numerous biological functions including host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. The protein encoded by this gene is expressed predominantly in the inner ear and is involved in the biogenesis of otoconia/otolith, which are crystalline structures of the inner ear involved in the perception of gravity.[provided by RefSeq, May 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOX3	NM_015718.3	c.512C>G	p.Thr171Arg	missense_variant	6/14	ENST00000159060.3	NP_056533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOX3	ENST00000159060.3	c.512C>G	p.Thr171Arg	missense_variant	6/14	1	NM_015718.3	ENSP00000159060.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.60
Sift	Benign	0.16	T
Sift4G	Benign	0.062	T
Polyphen		0.98	D
Vest4		0.58
MutPred		0.76		Loss of helix (P = 0.2022);
MVP		0.98
MPC		0.35
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.65
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs3749930; hg19: chr6-155761246;