Genetic Variant PAOX:p.Pro215Ser (chr10-133380460-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152911.4(PAOX):c.643C>T(p.Pro215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,610,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

PAOX
NM_152911.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34

Variant links:

Genes affected

PAOX (HGNC:20837): (polyamine oxidase) Enables polyamine oxidase activity. Involved in polyamine metabolic process and positive regulation of spermidine biosynthetic process. Predicted to be located in cytosol and peroxisomal matrix. [provided by Alliance of Genome Resources, Apr 2022]

PAOX links:

ENSG00000254536 (HGNC:):

ENSG00000254536 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAOX	NM_152911.4 link	c.643C>T	p.Pro215Ser	missense_variant	Exon 2 of 7	ENST00000278060.10	NP_690875.1	Q6QHF9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAOX	ENST00000278060.10 link	c.643C>T	p.Pro215Ser	missense_variant	Exon 2 of 7	1	NM_152911.4	ENSP00000278060.5	Q6QHF9-2
ENSG00000254536	ENST00000468317.3 link	n.256C>T		non_coding_transcript_exon_variant	Exon 1 of 16	5		ENSP00000436767.2	B0QZA9
ENSG00000254536	ENST00000670407.1 link	n.256C>T		non_coding_transcript_exon_variant	Exon 1 of 7			ENSP00000499264.1	A0A590UJ37

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000820

AC:

AN:

243916

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1458224

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

725542

show subpopulations

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:

0.0000702

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643C>T (p.P215S) alteration is located in exon 2 (coding exon 2) of the PAOX gene. This alteration results from a C to T substitution at nucleotide position 643, causing the proline (P) at amino acid position 215 to be replaced by a serine (S). 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

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.73

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.12

T;D;D

Polyphen

1.0

D;D;D

Vest4

0.57

MutPred

0.51

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.86

MPC

0.76

ClinPred

0.98

GERP RS

4.4

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over