11-89449498-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_016931.5(NOX4):c.291G>T(p.Leu97Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,611,924 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (14 hom.)
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.241

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05311069).
• BP6: Variant 11-89449498-C-A is Benign according to our data. Variant chr11-89449498-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 707952.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOX4	NM_016931.5	c.291G>T	p.Leu97Phe	missense_variant	4/18	ENST00000263317.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOX4	ENST00000263317.9	c.291G>T	p.Leu97Phe	missense_variant	4/18	1	NM_016931.5	P1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00153 AC: 379 AN: 247798 Hom.: 1 AF XY: 0.00151 AC XY: 203 AN XY: 134154

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000672

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00171

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00332 AC: 4850 AN: 1459688 Hom.: 14 Cov.: 29 AF XY: 0.00320 AC XY: 2324 AN XY: 726214

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00397

Gnomad4 OTH exome AF: 0.00332

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74448

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00313

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00312 Hom.: 1

Bravo AF: 0.00257

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00303 AC: 26

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00251

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	15
Dann	Uncertain	1.0
Eigen	Benign	-0.074
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.095	D
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	N;N;D;N;N;D;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.058	T;T;T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;D;T;T;T;T
Polyphen		0.028, 0.92, 0.13, 0.91	.;.;B;P;B;.;.;P
Vest4		0.73
MutPred		0.63		.;.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;
MVP		0.90
MPC		0.17
ClinPred		0.039	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139341533; hg19: chr11-89182666;