9-137423630-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001256067.2(NOXA1):​c.101C>T​(p.Pro34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,443,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: NOXA1 NM_001256067.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM1: In a mutagenesis_site Partial loss of function. (size 0) in uniprot entity NOXA1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.149815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOXA1	NM_001256067.2	c.101C>T	p.Pro34Leu	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>T	p.Pro34Leu	missense_variant	Exon 1 of 14		NM_001256067.2	ENSP00000507846.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151544 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000649 AC: 6 AN: 92436 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000774 AC: 10 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: 0.000329 AC: 9 AN: 27396

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

East Asian (EAS) AF: 0.00 AC: 0 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: 9.71e-7 AC: 1 AN: 1029404

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

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151544 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73982

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67808

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000192 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.101C>T (p.P34L) alteration is located in exon 1 (coding exon 1) of the NOXA1 gene. This alteration results from a C to T substitution at nucleotide position 101, causing the proline (P) at amino acid position 34 to be replaced by a leucine (L). 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	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		-0.43
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.043
Sift	Benign	0.16	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.92	P;P
Vest4		0.17
MutPred		0.42		Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP		0.29
MPC		2.1
ClinPred		0.53	D
GERP RS		0.48
PromoterAI		0.012	Neutral
gMVP		0.077
Mutation Taster		=96/4	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;