NM_001256067.2:c.380A>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/21 in silico tools predict a benign 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
• 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 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256067.2. 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
	NOXA1	NM_001256067.2	MANE Select	c.380A>G	p.Asn127Ser	missense	Exon 4 of 14	NP_001242996.1	Q86UR1-1
	NOXA1	NM_006647.2		c.380A>G	p.Asn127Ser	missense	Exon 4 of 14	NP_006638.1	Q86UR1-2
	NOXA1	NM_001256068.2		c.380A>G	p.Asn127Ser	missense	Exon 4 of 12	NP_001242997.1	Q86UR1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOXA1	ENST00000683555.1	MANE Select	c.380A>G	p.Asn127Ser	missense	Exon 4 of 14	ENSP00000507846.1	Q86UR1-1
	NOXA1	ENST00000341349.6	TSL:1	c.380A>G	p.Asn127Ser	missense	Exon 4 of 14	ENSP00000342848.2	Q86UR1-2
	NOXA1	ENST00000392815.2	TSL:1	c.380A>G	p.Asn127Ser	missense	Exon 4 of 12	ENSP00000376562.2	Q86UR1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000490 AC: 1 AN: 204006 AF XY: 0.00

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: 0.0000112

Gnomad OTH exome AF: 0.00

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

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

African (AFR) AF: 0.00 AC: 0 AN: 32798

American (AMR) AF: 0.00 AC: 0 AN: 41056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.00 AC: 0 AN: 38040

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5332

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1099160

Other (OTH) AF: 0.00 AC: 0 AN: 59256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00353856), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
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
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.63		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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1430180885; hg19: chr9-140323344;