9-137423659-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/19 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

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33280522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOXA1	NM_001256067.2	c.130G>A	p.Ala44Thr	missense_variant	1/14	ENST00000683555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOXA1	ENST00000683555.1	c.130G>A	p.Ala44Thr	missense_variant	1/14		NM_001256067.2	P1

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.89e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.130G>A (p.A44T) alteration is located in exon 1 (coding exon 1) of the NOXA1 gene. This alteration results from a G to A substitution at nucleotide position 130, causing the alanine (A) at amino acid position 44 to be replaced by a threonine (T). 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	-0.12	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;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.14
Sift	Benign	0.10	T;T
Sift4G	Benign	0.098	T;T
Polyphen		0.045	B;P
Vest4		0.17
MutPred		0.45		Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);
MVP		0.50
MPC		1.2
ClinPred		0.11	T
GERP RS		-1.7
gMVP		0.098

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

Publications

LitVar

Other links and lift over

dbSNP: rs1838677539; hg19: chr9-140318111;