6-155440112-G-T

Variant names:

• chr6-155440112-G-T
• rs3749930
• NM_015718.3:c.512C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015718.3(NOX3):​c.512C>A​(p.Thr171Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0791 in 1,602,040 control chromosomes in the GnomAD database, including 11,479 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.093 (1289 hom., cov: 32)
  • Exomes 𝑓: 0.078 (10190 hom.)
• Consequence: NOX3 NM_015718.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062431395).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOX3	NM_015718.3	c.512C>A	p.Thr171Lys	missense_variant	Exon 6 of 14	ENST00000159060.3	NP_056533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOX3	ENST00000159060.3	c.512C>A	p.Thr171Lys	missense_variant	Exon 6 of 14	1	NM_015718.3	ENSP00000159060.2

Frequencies

GnomAD3 genomes AF: 0.0931 AC: 14110 AN: 151600 Hom.: 1286 Cov.: 32

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.0681

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0842

GnomAD2 exomes AF: 0.136 AC: 32763 AN: 241652 AF XY: 0.132

Gnomad AFR exome AF: 0.0718

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.0666

Gnomad EAS exome AF: 0.510

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0964

GnomAD4 exome AF: 0.0776 AC: 112565 AN: 1450322 Hom.: 10190 Cov.: 32 AF XY: 0.0802 AC XY: 57790 AN XY: 720916

African (AFR) AF: 0.0738 AC: 2435 AN: 33004

American (AMR) AF: 0.234 AC: 10058 AN: 42932

Ashkenazi Jewish (ASJ) AF: 0.0676 AC: 1737 AN: 25694

East Asian (EAS) AF: 0.513 AC: 20192 AN: 39364

South Asian (SAS) AF: 0.190 AC: 15811 AN: 83256

European-Finnish (FIN) AF: 0.114 AC: 6047 AN: 53142

Middle Eastern (MID) AF: 0.0428 AC: 245 AN: 5728

European-Non Finnish (NFE) AF: 0.0458 AC: 50734 AN: 1107220

Other (OTH) AF: 0.0885 AC: 5306 AN: 59982

GnomAD4 genome AF: 0.0931 AC: 14120 AN: 151718 Hom.: 1289 Cov.: 32 AF XY: 0.103 AC XY: 7643 AN XY: 74118

African (AFR) AF: 0.0737 AC: 3048 AN: 41354

American (AMR) AF: 0.157 AC: 2396 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0681 AC: 236 AN: 3466

East Asian (EAS) AF: 0.501 AC: 2576 AN: 5144

South Asian (SAS) AF: 0.217 AC: 1040 AN: 4794

European-Finnish (FIN) AF: 0.123 AC: 1280 AN: 10414

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0492 AC: 3342 AN: 67970

Other (OTH) AF: 0.0857 AC: 181 AN: 2112

Alfa AF: 0.0677 Hom.: 2553

Bravo AF: 0.0979

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0431 AC: 166

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.0427 AC: 367

ExAC AF: 0.127 AC: 15419

Asia WGS AF: 0.324 AC: 1126 AN: 3478

EpiCase AF: 0.0413

EpiControl AF: 0.0427

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0062	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.44
Sift	Benign	0.096	T
Sift4G	Benign	0.069	T
Polyphen		0.98	D
Vest4		0.28
MPC		0.35
ClinPred		0.073	T
GERP RS		5.8
Varity_R		0.58
gMVP		0.87
Mutation Taster		=91/9	polymorphism (auto)

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: rs3749930; hg19: chr6-155761246; COSMIC: COSV50153415;