16-1979819-C-G

Variant names:

• chr16-1979819-C-G
• rs192494277
• NM_172167.3:c.671G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_172167.3(NOXO1):​c.671G>C​(p.Arg224Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,565,724 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R224W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (3 hom.)
• Consequence: NOXO1 NM_172167.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037693381).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.671G>C	p.Arg224Pro	missense	Exon 6 of 8	NP_751907.1	Q8NFA2-3
	TBL3	NM_006453.3	MANE Select	c.*1134C>G		3_prime_UTR	Exon 22 of 22	NP_006444.2
	NOXO1	NM_172168.3		c.686G>C	p.Arg229Pro	missense	Exon 6 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.671G>C	p.Arg224Pro	missense	Exon 6 of 8	ENSP00000348435.4	Q8NFA2-3
	NOXO1	ENST00000397280.8	TSL:1	c.686G>C	p.Arg229Pro	missense	Exon 6 of 8	ENSP00000380450.4	Q8NFA2-1
	NOXO1	ENST00000566005.5	TSL:1	c.683G>C	p.Arg228Pro	missense	Exon 6 of 8	ENSP00000456800.1	Q8NFA2-2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152280 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00673

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000518 AC: 91 AN: 175792 AF XY: 0.000472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.000644

GnomAD4 exome AF: 0.000134 AC: 190 AN: 1413326 Hom.: 3 Cov.: 32 AF XY: 0.000132 AC XY: 92 AN XY: 699432

African (AFR) AF: 0.00 AC: 0 AN: 32176

American (AMR) AF: 0.00 AC: 0 AN: 38504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00397 AC: 146 AN: 36804

South Asian (SAS) AF: 0.000234 AC: 19 AN: 81064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4752

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1089044

Other (OTH) AF: 0.000394 AC: 23 AN: 58414

GnomAD4 genome AF: 0.000262 AC: 40 AN: 152398 Hom.: 1 Cov.: 34 AF XY: 0.000295 AC XY: 22 AN XY: 74522

African (AFR) AF: 0.00 AC: 0 AN: 41602

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5186

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000224 Hom.: 0

Bravo AF: 0.000378

ExAC AF: 0.000405 AC: 48

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.11
DANN	Benign	0.70
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.76	N
PhyloP100		-2.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.14
Sift	Benign	0.27	T
Sift4G	Benign	0.32	T
Polyphen		0.57	P
Vest4		0.085
MVP		0.41
MPC		0.38
ClinPred		0.038	T
GERP RS		-9.5
Varity_R		0.13
gMVP		0.40
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs192494277; hg19: chr16-2029820;