chr9-137428892-A-G

Variant names:

• chr9-137428892-A-G
• rs1430180885
• NM_001256067.2:c.380A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001256067.2(NOXA1):​c.380A>G​(p.Asn127Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,432,574 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.380A>G	p.Asn127Ser	missense_variant	Exon 4 of 14	ENST00000683555.1	NP_001242996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOXA1	ENST00000683555.1	c.380A>G	p.Asn127Ser	missense_variant	Exon 4 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1432574 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380A>G (p.N127S) alteration is located in exon 4 (coding exon 4) of the NOXA1 gene. This alteration results from a A to G substitution at nucleotide position 380, causing the asparagine (N) at amino acid position 127 to be replaced by a serine (S). 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	19
DANN	Benign	0.84
Eigen	Benign	0.088
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.15
Sift	Benign	0.12	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.63		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.55
MPC		0.16
ClinPred		0.53	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1430180885; hg19: chr9-140323344;