rs12735723

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001122764.3(PPOX):c.767C>G(p.Pro256Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00894 in 1,614,136 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0092 ( 74 hom. )

Consequence

PPOX
NM_001122764.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:9

Conservation

PhyloP100: 2.31

Variant links:

Genes affected

PPOX (HGNC:9280): (protoporphyrinogen oxidase) This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. Mutations in this gene cause variegate porphyria, an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

PPOX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010694295).

BP6

Variant 1-161169143-C-G is Benign according to our data. Variant chr1-161169143-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8704.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr1-161169143-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00632 (962/152314) while in subpopulation NFE AF= 0.00994 (676/68024). AF 95% confidence interval is 0.00932. There are 5 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPOX	NM_001122764.3 linkuse as main transcript	c.767C>G	p.Pro256Arg	missense_variant	7/13	ENST00000367999.9	NP_001116236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPOX	ENST00000367999.9 linkuse as main transcript	c.767C>G	p.Pro256Arg	missense_variant	7/13	1	NM_001122764.3	ENSP00000356978	P1

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

962

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0125

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00994

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00614

AC:

1543

AN:

251274

Hom.:

AF XY:

0.00636

AC XY:

864

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.00976

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00921

AC:

13461

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00904

AC XY:

6576

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00188

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.0109

Gnomad4 OTH exome

AF:

0.00722

GnomAD4 genome

AF:

0.00632

AC:

962

AN:

152314

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

474

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00168

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0125

Gnomad4 NFE

AF:

0.00994

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00620

Hom.:

Bravo

AF:

0.00532

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00989

AC:

ExAC

AF:

0.00665

AC:

807

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00987

EpiControl

AF:

0.00901

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Variegate porphyria

Uncertain:1Benign:4

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000309.3:c.767C>G in the PPOX gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database, including eight homozygous occurrences. Functional studies indicated that this variant resulted in less than half of the normal PPOX activity in the prokaryotic expression system but the activity was almost normal in eukaryotic expression (PMID: 11286631). In addition, Whatley et al. reported this variant as a polymorphism (PMID: 10486317). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1; BS2; BS3. -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	curation	Department of Medical Genomics, Royal Prince Alfred Hospital	Jun 30, 2022	The PPOX:c.767C>G p.(Pro256Arg) variant has a gnomAD v2.1.1 FAF of 0.9288% (European non-Finnish). In a control population, allele frequency was 5%, with ~10% in the French cohort (Whatley et al 1999, PMID 10486317). In vitro functional studies found normal PPOX activity in transfected COS cells (Kauppinen et al 2001, PMID 11286631). in silico modelling predicts non-deleterious effect (REVEL score 0.495). Fulfils ACMG/AMP criteria BA1, BS3_supporting, BP4 and so is classified as Benign. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PPOX: BP4, BS1, BS2 -

Variegate porphyria, childhood-onset

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2001

- -

PPOX-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.63

D;D

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.15

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.79

P;P

Vest4

0.31

MVP

0.90

MPC

0.62

ClinPred

0.022

GERP RS

5.6

Varity_R

0.26

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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