rs12735723

chr1-161169143-C-Gchr1-161169143-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:9
• Conservation: PhyloP100: 2.31

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]

ACMG classification

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=2, 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 GnomAd at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPOX	NM_001122764.3	c.767C>G	p.Pro256Arg	missense_variant	7/13	ENST00000367999.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152196 Hom.: 5 Cov.: 32

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.: 7 AF XY: 0.00636 AC XY: 864 AN XY: 135838

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.: 74 Cov.: 31 AF XY: 0.00904 AC XY: 6576 AN XY: 727206

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.: 5 Cov.: 32 AF XY: 0.00636 AC XY: 474 AN XY: 74494

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.: 1

Bravo AF: 0.00532

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00989 AC: 85

ExAC AF: 0.00665 AC: 807

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.00901

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Variegate porphyria Uncertain:1 Benign:4

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, 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	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:4

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

Variegate porphyria, childhood-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2001

- -

PPOX-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Uncertain	0.63	D;D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs12735723; hg19: chr1-161138933; COSMIC: COSV57087672; COSMIC: COSV57087672;