9-137429324-C-T

Variant names:

• chr9-137429324-C-T
• rs755916333
• NM_001256067.2:c.553C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001256067.2(NOXA1):​c.553C>T​(p.Arg185Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,580,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.270

Genes affected

NOXA1 (HGNC:10668): (NADPH oxidase activator 1) This gene encodes a protein which activates NADPH oxidases, enzymes which catalyze a reaction generating reactive oxygen species. The encoded protein contains four N-terminal tetratricopeptide domains and a C-terminal Src homology 3 domain. Interaction between the encoded protein and proteins in the oxidase regulatory complex occur via the tetratricopeptide domains. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.553C>T	p.Arg185Trp	missense_variant	Exon 5 of 14	ENST00000683555.1	NP_001242996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOXA1	ENST00000683555.1	c.553C>T	p.Arg185Trp	missense_variant	Exon 5 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000409 AC: 8 AN: 195742 AF XY: 0.0000285

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000586

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 42 AN: 1428656 Hom.: 0 Cov.: 31 AF XY: 0.0000311 AC XY: 22 AN XY: 707390

Gnomad4 AFR exome AF: 0.0000604 AC: 2 AN: 33094

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 39092

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25324

Gnomad4 EAS exome AF: 0.0000261 AC: 1 AN: 38376

Gnomad4 SAS exome AF: 0.0000982 AC: 8 AN: 81442

Gnomad4 FIN exome AF: 0.0000202 AC: 1 AN: 49508

Gnomad4 NFE exome AF: 0.0000182 AC: 20 AN: 1096914

Gnomad4 Remaining exome AF: 0.000101 AC: 6 AN: 59206

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74344

Gnomad4 AFR AF: 0.0000724 AC: 0.0000723938 AN: 0.0000723938

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654022 AN: 0.0000654022

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192678 AN: 0.000192678

Gnomad4 SAS AF: 0.000207 AC: 0.000206954 AN: 0.000206954

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000146985 AN: 0.0000146985

Gnomad4 OTH AF: 0.000478 AC: 0.000477555 AN: 0.000477555

Alfa AF: 0.0000774 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000422 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.553C>T (p.R185W) alteration is located in exon 5 (coding exon 5) of the NOXA1 gene. This alteration results from a C to T substitution at nucleotide position 553, causing the arginine (R) at amino acid position 185 to be replaced by a tryptophan (W). 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
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.75
MPC		0.44
ClinPred		0.95	D
GERP RS		0.91
gMVP		0.74
Mutation Taster		=67/33	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

Publications

LitVar

Other links and lift over

dbSNP: rs755916333; hg19: chr9-140323776;