9-137423659-G-A

Variant names:

• chr9-137423659-G-A
• rs1838677539
• NM_001256067.2:c.130G>A

Variant summary

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

The NM_001256067.2(NOXA1):​c.130G>A​(p.Ala44Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000795 in 1,258,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 7.9e-7 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.631
• 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=0.33280522).

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.130G>A	p.Ala44Thr	missense	Exon 1 of 14	NP_001242996.1	Q86UR1-1
	NOXA1	NM_006647.2		c.130G>A	p.Ala44Thr	missense	Exon 1 of 14	NP_006638.1	Q86UR1-2
	NOXA1	NM_001256068.2		c.130G>A	p.Ala44Thr	missense	Exon 1 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.130G>A	p.Ala44Thr	missense	Exon 1 of 14	ENSP00000507846.1	Q86UR1-1
	NOXA1	ENST00000341349.6	TSL:1	c.130G>A	p.Ala44Thr	missense	Exon 1 of 14	ENSP00000342848.2	Q86UR1-2
	NOXA1	ENST00000392815.2	TSL:1	c.130G>A	p.Ala44Thr	missense	Exon 1 of 12	ENSP00000376562.2	Q86UR1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.95e-7 AC: 1 AN: 1258194 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 620442

⚠️ 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: 25836

American (AMR) AF: 0.00 AC: 0 AN: 23580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21070

East Asian (EAS) AF: 0.00 AC: 0 AN: 26668

South Asian (SAS) AF: 0.00 AC: 0 AN: 64090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4184

European-Non Finnish (NFE) AF: 9.89e-7 AC: 1 AN: 1010800

Other (OTH) AF: 0.00 AC: 0 AN: 50806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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	0.088
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.63
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Benign	0.098	T
Polyphen		0.045	B
Vest4		0.17
MutPred		0.45		Gain of helix (P = 0.2294)
MVP		0.50
MPC		1.2
ClinPred		0.11	T
GERP RS		-1.7
PromoterAI		0.041	Neutral
gMVP		0.098
Mutation Taster		=100/0	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: rs1838677539; hg19: chr9-140318111;