16-1979233-C-T

Variant names:

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

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]

NOXO1 links:

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]

TBL3 links:

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
NOXO1	NM_172167.3 link	c.935G>A	p.Gly312Asp	missense_variant	Exon 8 of 8	ENST00000356120.9	NP_751907.1	Q8NFA2-3A8K832
TBL3	NM_006453.3 link	c.*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
NOXO1	ENST00000356120.9 link	c.935G>A	p.Gly312Asp	missense_variant	Exon 8 of 8	1	NM_172167.3	ENSP00000348435.4		Q8NFA2-3
TBL3	ENST00000568546.6 link	c.*548C>T		3_prime_UTR_variant	Exon 22 of 22	1	NM_006453.3	ENSP00000454836.1		Q12788

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

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:

AN:

105864

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1353414

Hom.:

Cov.:

AF XY:

0.00000300

AC XY:

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:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

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

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

LIST_S2

Benign

0.41

T;T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.063

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

.;.;N;.

PrimateAI

Uncertain

0.60

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over