NM_172167.3:c.781G>C

Variant names:

• chr16-1979462-C-G
• NM_172167.3:c.781G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_172167.3(NOXO1):​c.781G>C​(p.Val261Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: NOXO1 NM_172167.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172167.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOXO1	NM_172167.3	MANE Select	c.781G>C	p.Val261Leu	missense	Exon 7 of 8	NP_751907.1	Q8NFA2-3
	TBL3	NM_006453.3	MANE Select	c.*777C>G		3_prime_UTR	Exon 22 of 22	NP_006444.2
	NOXO1	NM_172168.3		c.796G>C	p.Val266Leu	missense	Exon 7 of 8	NP_751908.1	Q8NFA2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOXO1	ENST00000356120.9	TSL:1 MANE Select	c.781G>C	p.Val261Leu	missense	Exon 7 of 8	ENSP00000348435.4	Q8NFA2-3
	NOXO1	ENST00000397280.8	TSL:1	c.796G>C	p.Val266Leu	missense	Exon 7 of 8	ENSP00000380450.4	Q8NFA2-1
	NOXO1	ENST00000566005.5	TSL:1	c.793G>C	p.Val265Leu	missense	Exon 7 of 8	ENSP00000456800.1	Q8NFA2-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.37
Sift	Benign	0.068	T
Sift4G	Uncertain	0.017	D
Polyphen		0.99	D
Vest4		0.70
MutPred		0.82		Loss of MoRF binding (P = 0.1011)
MVP		0.65
MPC		0.92
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.48
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr16-2029463;