11-89340101-G-A

Position:

• chr11-89340101-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016931.5(NOX4):​c.1408C>T​(p.Arg470Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,573,164 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.936

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015197724).
• BP6: Variant 11-89340101-G-A is Benign according to our data. Variant chr11-89340101-G-A is described in ClinVar as [Benign]. Clinvar id is 786601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00548 (833/152120) while in subpopulation AFR AF= 0.0187 (778/41510). AF 95% confidence interval is 0.0177. There are 8 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOX4	NM_016931.5	c.1408C>T	p.Arg470Cys	missense_variant	15/18	ENST00000263317.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOX4	ENST00000263317.9	c.1408C>T	p.Arg470Cys	missense_variant	15/18	1	NM_016931.5	P1

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 828 AN: 152002 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00127 AC: 265 AN: 209308 Hom.: 4 AF XY: 0.000866 AC XY: 99 AN XY: 114338

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.000992

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000963

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.000628

GnomAD4 exome AF: 0.000563 AC: 800 AN: 1421044 Hom.: 7 Cov.: 28 AF XY: 0.000468 AC XY: 331 AN XY: 706560

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000503

Gnomad4 FIN exome AF: 0.0000568

Gnomad4 NFE exome AF: 0.0000219

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00548 AC: 833 AN: 152120 Hom.: 8 Cov.: 32 AF XY: 0.00527 AC XY: 392 AN XY: 74346

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.00269

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00653

ESP6500AA AF: 0.0173 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Uncertain	0.68	.;.;.;.;D;.;.;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.80	T;.;T;T;T;T;.;T;T;T
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0079	T
MutationAssessor	Benign	0.0	.;.;.;.;N;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.20	T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T;T;T;T;D;T;D
Polyphen		0.0040, 0.37, 0.0010, 0.0030, 0.0, 0.99	.;.;B;B;B;.;.;B;B;D
Vest4		0.29
MVP		0.89
MPC		0.059
ClinPred		0.037	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs115031759; hg19: chr11-89073269; COSMIC: COSV99629184; COSMIC: COSV99629184;