chr1-161169143-C-G

Variant names:

• chr1-161169143-C-G
• rs12735723
• NM_001122764.3:c.767C>G

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• variegate porphyria

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPOX	NM_001122764.3	c.767C>G	p.Pro256Arg	missense_variant	Exon 7 of 13	ENST00000367999.9	NP_001116236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPOX	ENST00000367999.9	c.767C>G	p.Pro256Arg	missense_variant	Exon 7 of 13	1	NM_001122764.3	ENSP00000356978.4

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

GnomAD2 exomes AF: 0.00614 AC: 1543 AN: 251274 AF XY: 0.00636

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 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

African (AFR) AF: 0.00111 AC: 37 AN: 33478

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00188 AC: 162 AN: 86258

European-Finnish (FIN) AF: 0.0111 AC: 592 AN: 53360

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0109 AC: 12111 AN: 1112006

Other (OTH) AF: 0.00722 AC: 436 AN: 60392

GnomAD4 genome AF: 0.00632 AC: 962 AN: 152314 Hom.: 5 Cov.: 32 AF XY: 0.00636 AC XY: 474 AN XY: 74494

African (AFR) AF: 0.00168 AC: 70 AN: 41558

American (AMR) AF: 0.00431 AC: 66 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00994 AC: 676 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

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

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2022

Department of Medical Genomics, Royal Prince Alfred Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:4

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PPOX: BP4, BS1, BS2 -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Variegate porphyria, childhood-onset Pathogenic:1

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PPOX-related disorder Benign:1

May 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
LIST_S2	Uncertain	0.88	.;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		2.3
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
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

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