11-89354977-G-T

Variant names:

• chr11-89354977-G-T
• rs138335737
• NM_016931.5:c.1202C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016931.5(NOX4):​c.1202C>A​(p.Ser401Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000274 in 1,592,236 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: NOX4 NM_016931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26168314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOX4	NM_016931.5	c.1202C>A	p.Ser401Tyr	missense_variant	Exon 13 of 18	ENST00000263317.9	NP_058627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOX4	ENST00000263317.9	c.1202C>A	p.Ser401Tyr	missense_variant	Exon 13 of 18	1	NM_016931.5	ENSP00000263317.4

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000318 AC: 78 AN: 245540 Hom.: 0 AF XY: 0.000339 AC XY: 45 AN XY: 132922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.000699

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000269 AC: 388 AN: 1440146 Hom.: 1 Cov.: 24 AF XY: 0.000297 AC XY: 213 AN XY: 717426

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.000810

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000588

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000310

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152090 Hom.: 1 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000363 AC: 44

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1202C>A (p.S401Y) alteration is located in exon 13 (coding exon 13) of the NOX4 gene. This alteration results from a C to A substitution at nucleotide position 1202, causing the serine (S) at amino acid position 401 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.34
DEOGEN2	Benign	0.30	.;.;.;T;.;.;.;.;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.3	.;.;L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.4	N;N;N;N;N;N;D;N;N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;T;D;T;D;D;T;T;T
Sift4G	Benign	0.067	T;T;T;T;T;T;T;T;T;T
Polyphen		0.061, 0.39, 0.27, 0.16, 0.76, 0.89	.;.;B;B;.;.;B;B;P;P
Vest4		0.53
MVP		0.95
MPC		0.085
ClinPred		0.045	T
GERP RS		5.3
Varity_R		0.25
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs138335737; hg19: chr11-89088145;