16-1979128-A-C

Variant names:

• chr16-1979128-A-C
• rs2083439713
• NM_172167.3:c.1040T>G

Variant summary

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

The NM_172167.3(NOXO1):​c.1040T>G​(p.Leu347Arg) 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: 34)
  • Exomes 𝑓: 0.0000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOXO1 NM_172167.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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]

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=0.19458222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXO1	NM_172167.3	c.1040T>G	p.Leu347Arg	missense_variant	Exon 8 of 8	ENST00000356120.9	NP_751907.1
TBL3	NM_006453.3	c.*443A>C		3_prime_UTR_variant	Exon 22 of 22	ENST00000568546.6	NP_006444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOXO1	ENST00000356120.9	c.1040T>G	p.Leu347Arg	missense_variant	Exon 8 of 8	1	NM_172167.3	ENSP00000348435.4
TBL3	ENST00000568546.6	c.*443A>C		3_prime_UTR_variant	Exon 22 of 22	1	NM_006453.3	ENSP00000454836.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000460 AC: 6 AN: 1303786 Hom.: 0 Cov.: 33 AF XY: 0.00000156 AC XY: 1 AN XY: 642994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000466

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000478

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1055T>G (p.L352R) alteration is located in exon 8 (coding exon 8) of the NOXO1 gene. This alteration results from a T to G substitution at nucleotide position 1055, causing the leucine (L) at amino acid position 352 to be replaced by an arginine (R). 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	0.15
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;.;D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.50	T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.5	.;.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.96	D;D;P;D
Vest4		0.45
MutPred		0.34		.;.;Loss of helix (P = 0.0033);.;
MVP		0.68
MPC		0.94
ClinPred		0.81	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.52
gMVP		0.56

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: rs2083439713; hg19: chr16-2029129;