9-137423576-A-G

Variant names:

• chr9-137423576-A-G
• rs753867593
• NM_001256067.2:c.47A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256067.2(NOXA1):​c.47A>G​(p.Gln16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,463,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. Q16E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.122
• Publications: 1 publications found

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.100949705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.47A>G	p.Gln16Arg	missense_variant	Exon 1 of 14	ENST00000683555.1	NP_001242996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOXA1	ENST00000683555.1	c.47A>G	p.Gln16Arg	missense_variant	Exon 1 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151286 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 4 AN: 143526 AF XY: 0.0000241

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.0000908

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000381 AC: 5 AN: 1312132 Hom.: 0 Cov.: 31 AF XY: 0.00000460 AC XY: 3 AN XY: 651580

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000728 AC: 2 AN: 27488

American (AMR) AF: 0.0000621 AC: 2 AN: 32194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22004

East Asian (EAS) AF: 0.00 AC: 0 AN: 29762

South Asian (SAS) AF: 0.00 AC: 0 AN: 69968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4912

European-Non Finnish (NFE) AF: 9.63e-7 AC: 1 AN: 1038842

Other (OTH) AF: 0.00 AC: 0 AN: 52840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000819), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000397 AC: 6 AN: 151286 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2 AN XY: 73876

African (AFR) AF: 0.000145 AC: 6 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67762

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00000873 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47A>G (p.Q16R) alteration is located in exon 1 (coding exon 1) of the NOXA1 gene. This alteration results from a A to G substitution at nucleotide position 47, causing the glutamine (Q) at amino acid position 16 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
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.86
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.58	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		0.12
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.080
Sift	Benign	0.19	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.84	P;P
Vest4		0.12
MutPred		0.42		Gain of MoRF binding (P = 0.0093);Gain of MoRF binding (P = 0.0093);
MVP		0.39
MPC		2.2
ClinPred		0.11	T
GERP RS		1.7
PromoterAI		-0.063	Neutral
gMVP		0.17
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs753867593; hg19: chr9-140318028;