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GeneBe

15-69028321-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024505.4(NOX5):c.281C>T(p.Pro94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

NOX5
NM_024505.4 missense

Scores

1
1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.78
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.15677842).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOX5NM_024505.4 linkuse as main transcriptc.281C>T p.Pro94Leu missense_variant 3/16 ENST00000388866.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOX5ENST00000388866.8 linkuse as main transcriptc.281C>T p.Pro94Leu missense_variant 3/161 NM_024505.4 Q96PH1-1
NOX5ENST00000530406.7 linkuse as main transcriptc.281C>T p.Pro94Leu missense_variant 3/161 P1Q96PH1-3
NOX5ENST00000527315.5 linkuse as main transcriptn.285C>T non_coding_transcript_exon_variant 3/152

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000132
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000440
AC:
11
AN:
249980
Hom.:
0
AF XY:
0.0000444
AC XY:
6
AN XY:
135102
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000885
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000342
AC:
50
AN:
1460526
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
726580
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000378
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000988
Hom.:
0
Bravo
AF:
0.0000982
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 12, 2022The c.281C>T (p.P94L) alteration is located in exon 3 (coding exon 3) of the NOX5 gene. This alteration results from a C to T substitution at nucleotide position 281, causing the proline (P) at amino acid position 94 to be replaced by a leucine (L). 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
0.18
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.45
Cadd
Benign
8.1
Dann
Benign
0.64
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.056
N
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.16
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Pathogenic
-5.1
D;D;D;D;D
REVEL
Benign
0.10
Sift
Benign
0.058
T;D;T;D;T
Sift4G
Benign
0.085
T;T;T;T;T
Polyphen
0.42, 0.29, 0.23
.;.;B;B;B
Vest4
0.27
MutPred
0.48
.;.;.;Loss of methylation at K99 (P = 0.0728);Loss of methylation at K99 (P = 0.0728);
MVP
0.59
MPC
0.31
ClinPred
0.80
D
GERP RS
2.8
Varity_R
0.057
gMVP
0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759200679; hg19: chr15-69320661; COSMIC: COSV52997227; COSMIC: COSV52997227; API