16-1979233-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_172167.3(NOXO1):​c.935G>A​(p.Gly312Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000598 in 1,505,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

NOXO1
NM_172167.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0250
Variant links:
Genes affected
NOXO1 (HGNC:19404): (NADPH oxidase organizer 1) This gene encodes an NADPH oxidase (NOX) organizer, which positively regulates NOX1 and NOX3. The protein contains a PX domain and two SH3 domains. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2012]
TBL3 (HGNC:11587): (transducin beta like 3) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This gene has multiple polyadenylation sites. It might have multiple alternatively spliced transcript variants but the variants have not been fully described yet. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06264305).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOXO1NM_172167.3 linkc.935G>A p.Gly312Asp missense_variant Exon 8 of 8 ENST00000356120.9 NP_751907.1 Q8NFA2-3A8K832
TBL3NM_006453.3 linkc.*548C>T 3_prime_UTR_variant Exon 22 of 22 ENST00000568546.6 NP_006444.2 Q12788

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOXO1ENST00000356120.9 linkc.935G>A p.Gly312Asp missense_variant Exon 8 of 8 1 NM_172167.3 ENSP00000348435.4 Q8NFA2-3
TBL3ENST00000568546.6 linkc.*548C>T 3_prime_UTR_variant Exon 22 of 22 1 NM_006453.3 ENSP00000454836.1 Q12788

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152186
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000945
AC:
1
AN:
105864
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
58896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000497
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000443
AC:
6
AN:
1353414
Hom.:
0
Cov.:
35
AF XY:
0.00000300
AC XY:
2
AN XY:
666348
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000645
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000281
Gnomad4 OTH exome
AF:
0.0000177
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152186
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.950G>A (p.G317D) alteration is located in exon 8 (coding exon 8) of the NOXO1 gene. This alteration results from a G to A substitution at nucleotide position 950, causing the glycine (G) at amino acid position 317 to be replaced by an aspartic acid (D). 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
0.070
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
7.0
DANN
Benign
0.78
DEOGEN2
Benign
0.093
.;.;T;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.41
T;T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.063
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
.;.;N;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.18
N;N;N;N
REVEL
Benign
0.054
Sift
Benign
0.19
T;T;T;T
Sift4G
Benign
0.31
T;T;T;T
Polyphen
0.017
B;B;B;B
Vest4
0.031
MutPred
0.14
.;.;Gain of relative solvent accessibility (P = 0.09);.;
MVP
0.40
MPC
0.34
ClinPred
0.037
T
GERP RS
0.070
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.9
Varity_R
0.056
gMVP
0.23

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

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

Other links and lift over

dbSNP: rs1272494983; hg19: chr16-2029234; API