9-137428886-T-C

Variant names:

• chr9-137428886-T-C
• rs1229353768
• NM_001256067.2:c.374T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001256067.2(NOXA1):​c.374T>C​(p.Leu125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.643
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

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.374T>C	p.Leu125Pro	missense	Exon 4 of 14	NP_001242996.1	Q86UR1-1
	NOXA1	NM_006647.2		c.374T>C	p.Leu125Pro	missense	Exon 4 of 14	NP_006638.1	Q86UR1-2
	NOXA1	NM_001256068.2		c.374T>C	p.Leu125Pro	missense	Exon 4 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.374T>C	p.Leu125Pro	missense	Exon 4 of 14	ENSP00000507846.1	Q86UR1-1
	NOXA1	ENST00000341349.6	TSL:1	c.374T>C	p.Leu125Pro	missense	Exon 4 of 14	ENSP00000342848.2	Q86UR1-2
	NOXA1	ENST00000392815.2	TSL:1	c.374T>C	p.Leu125Pro	missense	Exon 4 of 12	ENSP00000376562.2	Q86UR1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428714 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 708242

African (AFR) AF: 0.00 AC: 0 AN: 32668

American (AMR) AF: 0.00 AC: 0 AN: 40512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37772

South Asian (SAS) AF: 0.00 AC: 0 AN: 81844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097394

Other (OTH) AF: 0.00 AC: 0 AN: 59152

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	0.096
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.64
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.81		Loss of stability (P = 0.0289)
MVP		0.58
MPC		0.54
ClinPred		0.93	D
GERP RS		1.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
gMVP		0.91
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1229353768; hg19: chr9-140323338;