rs121918324

Variant names:

• chr1-161167187-C-T
• rs121918324
• NM_001122764.3:c.175C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001350129.2(PPOX):​c.-253C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PPOX NM_001350129.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 1.39

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-161167187-C-T is Pathogenic according to our data. Variant chr1-161167187-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161167187-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPOX	NM_001122764.3	c.175C>T	p.Arg59Trp	missense_variant	Exon 3 of 13	ENST00000367999.9	NP_001116236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPOX	ENST00000367999.9	c.175C>T	p.Arg59Trp	missense_variant	Exon 3 of 13	1	NM_001122764.3	ENSP00000356978.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461892 Hom.: 0 Cov.: 38 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Variegate porphyria Pathogenic:2 Other:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with porphyria variegate (MIM#176200). (I) 0107 - This gene is associated with autosomal dominant disease. Double heterozygotes have been reported (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews, PMID: 21910705). (I) 0115 - Variants in this gene are known to have variable expressivity. Symptoms are more common in women, and acute manifestations are highly variable and can become chronic (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated amino-oxidase domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is known as a founder allele introduced by the Dutch settlers to South Africa, where it accounts for 95% of variegate porphyria cases (GeneReviews, PMID: 21910705). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 59 of the PPOX protein (p.Arg59Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with variegate porphyria (PMID: 8673113, 8817334). It is commonly reported in individuals of South African ancestry (PMID: 8673113, 8817334). ClinVar contains an entry for this variant (Variation ID: 8696). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PPOX protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PPOX function (PMID: 12922165). For these reasons, this variant has been classified as Pathogenic. -

Variegate porphyria, childhood-onset Pathogenic:1

Aug 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.97	.;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.7	D;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;D;.;D
Vest4		0.76
MutPred		0.90		Loss of disorder (P = 0.025);Loss of disorder (P = 0.025);Loss of disorder (P = 0.025);Loss of disorder (P = 0.025);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs121918324; hg19: chr1-161136977; COSMIC: COSV57090035; COSMIC: COSV57090035;