9-137423630-C-G

Variant names:

• chr9-137423630-C-G
• rs749850148
• NM_001256067.2:c.101C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001256067.2(NOXA1):​c.101C>G​(p.Pro34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000774 in 1,291,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. P34L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.426
• 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.

• PM1: In a mutagenesis_site Partial loss of function. (size 0) in uniprot entity NOXA1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07110751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.101C>G	p.Pro34Arg	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.101C>G	p.Pro34Arg	missense_variant	Exon 1 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.74e-7 AC: 1 AN: 1291704 Hom.: 0 Cov.: 31 AF XY: 0.00000157 AC XY: 1 AN XY: 638726

African (AFR) AF: 0.00 AC: 0 AN: 26544

American (AMR) AF: 0.00 AC: 0 AN: 27396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21954

East Asian (EAS) AF: 0.0000366 AC: 1 AN: 27316

South Asian (SAS) AF: 0.00 AC: 0 AN: 69482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1029404

Other (OTH) AF: 0.00 AC: 0 AN: 52428

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.97
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.68	N;N
PhyloP100		-0.43
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.022
Sift	Benign	0.51	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.040	B;B
Vest4		0.20
MutPred		0.45		Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);
MVP		0.16
MPC		1.3
ClinPred		0.051	T
GERP RS		0.48
PromoterAI		-0.0079	Neutral
gMVP		0.042
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs749850148; hg19: chr9-140318082;