rs121918326

Variant names:

• chr1-161166906-A-C
• rs121918326
• NM_001122764.3:c.59A>C
• PPOX p.His20Pro

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001122764.3(PPOX):​c.59A>C​(p.His20Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPOX NM_001122764.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.13
• Publications: 6 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, SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-161166906-A-C is Pathogenic according to our data. Variant chr1-161166906-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8695.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	NM_001122764.3	MANE Select	c.59A>C	p.His20Pro	missense	Exon 2 of 13	NP_001116236.1	P50336
	PPOX	NM_000309.5		c.59A>C	p.His20Pro	missense	Exon 2 of 13	NP_000300.1	P50336
	PPOX	NM_001365398.1		c.59A>C	p.His20Pro	missense	Exon 2 of 13	NP_001352327.1	P50336

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	ENST00000367999.9	TSL:1 MANE Select	c.59A>C	p.His20Pro	missense	Exon 2 of 13	ENSP00000356978.4	P50336
	PPOX	ENST00000352210.9	TSL:1	c.59A>C	p.His20Pro	missense	Exon 2 of 13	ENSP00000343943.5	P50336
	PPOX	ENST00000881040.1		c.59A>C	p.His20Pro	missense	Exon 2 of 14	ENSP00000551099.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000655 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Variegate porphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.026	D
PromoterAI		0.068	Neutral
Varity_R		0.97
gMVP		0.96
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121918326;

hg19: chr1-161136696;

COSMIC: COSV57086951;

COSMIC: COSV57086951;