9-137428937-C-T

Variant names:

• chr9-137428937-C-T
• rs151149799
• NM_001256067.2:c.425C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001256067.2(NOXA1):​c.425C>T​(p.Ala142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 1,597,002 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.631
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012951195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.425C>T	p.Ala142Val	missense_variant	Exon 4 of 14	ENST00000683555.1	NP_001242996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOXA1	ENST00000683555.1	c.425C>T	p.Ala142Val	missense_variant	Exon 4 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 24 AN: 219208 AF XY: 0.0000756

Gnomad AFR exome AF: 0.000378

Gnomad AMR exome AF: 0.0000314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.0000450 AC: 65 AN: 1444844 Hom.: 0 Cov.: 32 AF XY: 0.0000348 AC XY: 25 AN XY: 717394

African (AFR) AF: 0.000151 AC: 5 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 42668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.000386 AC: 15 AN: 38894

South Asian (SAS) AF: 0.00 AC: 0 AN: 83428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50740

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1104868

Other (OTH) AF: 0.000687 AC: 41 AN: 59704

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.000121 AC: 5 AN: 41430

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

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

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.425C>T (p.A142V) alteration is located in exon 4 (coding exon 4) of the NOXA1 gene. This alteration results from a C to T substitution at nucleotide position 425, causing the alanine (A) at amino acid position 142 to be replaced by a valine (V). 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	-0.50	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.9
DANN	Uncertain	0.99
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		-0.63
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.038
Sift	Benign	0.21	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.67	P;D
Vest4		0.17
MVP		0.24
MPC		0.079
ClinPred		0.012	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151149799; hg19: chr9-140323389; COSMIC: COSV106062107;