rs121918326

Positions:

• chr1-161166906-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000367999.9(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 ENST00000367999.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.13

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 Likely_pathogenic. Variant got 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 id is 8695.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPOX	NM_001122764.3	c.59A>C	p.His20Pro	missense_variant	2/13	ENST00000367999.9	NP_001116236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPOX	ENST00000367999.9	c.59A>C	p.His20Pro	missense_variant	2/13	1	NM_001122764.3	ENSP00000356978	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Variegate porphyria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.
MutationTaster	Benign	0.99	A;A;A;A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;D;.;N;N;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.016	D;D;.;T;D;.
Sift4G	Uncertain	0.026	D;D;.;D;D;.
Polyphen		0.87	P;P;.;P;.;.
Vest4		0.66
MutPred		0.90		Gain of glycosylation at H20 (P = 0.0227);Gain of glycosylation at H20 (P = 0.0227);Gain of glycosylation at H20 (P = 0.0227);Gain of glycosylation at H20 (P = 0.0227);Gain of glycosylation at H20 (P = 0.0227);Gain of glycosylation at H20 (P = 0.0227);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918326; hg19: chr1-161136696; COSMIC: COSV57086951; COSMIC: COSV57086951;