15-69028337-A-C

Position:

• chr15-69028337-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024505.4(NOX5):​c.297A>C​(p.Lys99Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOX5 NM_024505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.699

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25153312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOX5	NM_024505.4	c.297A>C	p.Lys99Asn	missense_variant	3/16	ENST00000388866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOX5	ENST00000388866.8	c.297A>C	p.Lys99Asn	missense_variant	3/16	1	NM_024505.4
NOX5	ENST00000530406.7	c.297A>C	p.Lys99Asn	missense_variant	3/16	1		P1
NOX5	ENST00000527315.5	n.301A>C		non_coding_transcript_exon_variant	3/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.297A>C (p.K99N) alteration is located in exon 3 (coding exon 3) of the NOX5 gene. This alteration results from a A to C substitution at nucleotide position 297, causing the lysine (K) at amino acid position 99 to be replaced by an asparagine (N). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;.;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	.;.;.;L;L
MutationTaster	Benign	0.90	N;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Benign	0.067
Sift	Benign	0.086	T;T;T;T;T
Sift4G	Benign	0.077	T;T;T;T;T
Polyphen		0.80, 0.17, 0.066	.;.;P;B;B
Vest4		0.44
MutPred		0.46		.;.;.;Loss of ubiquitination at K99 (P = 0.0218);Loss of ubiquitination at K99 (P = 0.0218);
MVP		0.76
MPC		0.30
ClinPred		0.95	D
GERP RS		-0.16
Varity_R		0.19
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-69320677;