chr9-137423657-A-C

Variant names:

• chr9-137423657-A-C
• rs766036724
• NM_001256067.2:c.128A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001256067.2(NOXA1):​c.128A>C​(p.Asn43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000652 in 1,411,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.128A>C	p.Asn43Thr	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.128A>C	p.Asn43Thr	missense_variant	Exon 1 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 42 AN: 151476 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000801 AC: 6 AN: 74876 AF XY: 0.0000456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000692

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000381 AC: 48 AN: 1259848 Hom.: 0 Cov.: 31 AF XY: 0.0000370 AC XY: 23 AN XY: 621354

African (AFR) AF: 0.00124 AC: 32 AN: 25892

American (AMR) AF: 0.000168 AC: 4 AN: 23870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21122

East Asian (EAS) AF: 0.00 AC: 0 AN: 26714

South Asian (SAS) AF: 0.00 AC: 0 AN: 64358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4214

European-Non Finnish (NFE) AF: 0.00000395 AC: 4 AN: 1011552

Other (OTH) AF: 0.000157 AC: 8 AN: 50870

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151584 Hom.: 0 Cov.: 33 AF XY: 0.000310 AC XY: 23 AN XY: 74086

African (AFR) AF: 0.00104 AC: 43 AN: 41454

American (AMR) AF: 0.0000657 AC: 1 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67804

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000351

ExAC AF: 0.0000211 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.128A>C (p.N43T) alteration is located in exon 1 (coding exon 1) of the NOXA1 gene. This alteration results from a A to C substitution at nucleotide position 128, causing the asparagine (N) at amino acid position 43 to be replaced by a threonine (T). 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	-0.38	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Benign	0.95
Eigen	Benign	0.053
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		1.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;P
Vest4		0.62
MutPred		0.84		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP		0.76
MPC		2.2
ClinPred		0.29	T
GERP RS		3.2
PromoterAI		-0.047	Neutral
gMVP		0.61
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766036724; hg19: chr9-140318109;