rs7168025

Positions:

• chr15-69056673-A-G

Variant summary

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

The ENST00000388866.8(NOX5):​c.2275A>G​(p.Arg759Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,820 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0095 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (24 hom.)
• Consequence: NOX5 ENST00000388866.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.335

Genes affected

NOX5 (HGNC:14874): (NADPH oxidase 5) This gene is predominantly expressed in the testis and lymphocyte-rich areas of spleen and lymph nodes. It encodes a calcium-dependen NADPH oxidase that generates superoxide, and functions as a calcium-dependent proton channel that may regulate redox-dependent processes in lymphocytes and spermatozoa. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003063202).
• BP6: Variant 15-69056673-A-G is Benign according to our data. Variant chr15-69056673-A-G is described in ClinVar as [Benign]. Clinvar id is 785499.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 = 0.00946 (1440/152290) while in subpopulation AFR AF= 0.0334 (1389/41542). AF 95% confidence interval is 0.032. There are 27 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOX5	NM_024505.4	c.2275A>G	p.Arg759Gly	missense_variant	16/16	ENST00000388866.8	NP_078781.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOX5	ENST00000388866.8	c.2275A>G	p.Arg759Gly	missense_variant	16/16	1	NM_024505.4	ENSP00000373518
NOX5	ENST00000530406.7	c.2191A>G	p.Arg731Gly	missense_variant	16/16	1		ENSP00000432440	P1
NOX5	ENST00000525143.5	c.*657A>G		3_prime_UTR_variant, NMD_transcript_variant	12/12	1		ENSP00000455703
NOX5	ENST00000527315.5	n.5431A>G		non_coding_transcript_exon_variant	15/15	2

Frequencies

GnomAD3 genomes AF: 0.00946 AC: 1440 AN: 152172 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00251 AC: 631 AN: 251364 Hom.: 13 AF XY: 0.00188 AC XY: 256 AN XY: 135846

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000974 AC: 1423 AN: 1461530 Hom.: 24 Cov.: 30 AF XY: 0.000858 AC XY: 624 AN XY: 727074

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00946 AC: 1440 AN: 152290 Hom.: 27 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74470

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00183 Hom.: 10

Bravo AF: 0.0104

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00306 AC: 372

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.76
DANN	Benign	0.22
DEOGEN2	Benign	0.15	.;.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;.;L;.
MutationTaster	Benign	0.80	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.38	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.15, 0.094	.;.;B;B;B
Vest4		0.16
MVP		0.37
MPC		0.33
ClinPred		0.0071	T
GERP RS		0.52
Varity_R		0.053
gMVP		0.37

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: rs7168025; hg19: chr15-69349013;