9-137429312-G-C

Variant names:

• chr9-137429312-G-C
• rs1838985798
• NM_001256067.2:c.541G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256067.2(NOXA1):​c.541G>C​(p.Gly181Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G181S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35683584).

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.541G>C	p.Gly181Arg	missense	Exon 5 of 14	NP_001242996.1	Q86UR1-1
	NOXA1	NM_006647.2		c.541G>C	p.Gly181Arg	missense	Exon 5 of 14	NP_006638.1	Q86UR1-2
	NOXA1	NM_001256068.2		c.504+296G>C		intron	N/A	NP_001242997.1	Q86UR1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOXA1	ENST00000683555.1	MANE Select	c.541G>C	p.Gly181Arg	missense	Exon 5 of 14	ENSP00000507846.1	Q86UR1-1
	NOXA1	ENST00000341349.6	TSL:1	c.541G>C	p.Gly181Arg	missense	Exon 5 of 14	ENSP00000342848.2	Q86UR1-2
	NOXA1	ENST00000392815.2	TSL:1	c.504+296G>C		intron	N/A	ENSP00000376562.2	Q86UR1-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.33		Gain of MoRF binding (P = 0.0127)
MVP		0.70
MPC		0.47
ClinPred		0.97	D
GERP RS		3.3
gMVP		0.71
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1838985798; hg19: chr9-140323764;