NM_001122764.3:c.767C>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 VariationId is 8704.
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122764.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	NM_001122764.3	MANE Select	c.767C>G	p.Pro256Arg	missense	Exon 7 of 13	NP_001116236.1
	PPOX	NM_000309.5		c.767C>G	p.Pro256Arg	missense	Exon 7 of 13	NP_000300.1
	PPOX	NM_001365398.1		c.767C>G	p.Pro256Arg	missense	Exon 7 of 13	NP_001352327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	ENST00000367999.9	TSL:1 MANE Select	c.767C>G	p.Pro256Arg	missense	Exon 7 of 13	ENSP00000356978.4
	PPOX	ENST00000352210.9	TSL:1	c.767C>G	p.Pro256Arg	missense	Exon 7 of 13	ENSP00000343943.5
	PPOX	ENST00000652182.1		c.767C>G	p.Pro256Arg	missense	Exon 7 of 12	ENSP00000498884.1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Variegate porphyria (5)
-	-	4	not provided (4)
-	-	1	PPOX-related disorder (1)
1	-	-	Variegate porphyria, childhood-onset (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.49
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.79	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;