rs121918324

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001405291: Experimental studies have shown that this missense change affects PPOX function (PMID:12922165).".

• 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
• Publications: 30 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001405291: Experimental studies have shown that this missense change affects PPOX function (PMID: 12922165).
• 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 VariationId is 8696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350129.2. 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.175C>T	p.Arg59Trp	missense	Exon 3 of 13	NP_001116236.1	P50336
	PPOX	NM_001350129.2		c.-253C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001337058.1
	PPOX	NM_001365400.1		c.-137C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001352329.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	ENST00000367999.9	TSL:1 MANE Select	c.175C>T	p.Arg59Trp	missense	Exon 3 of 13	ENSP00000356978.4	P50336
	PPOX	ENST00000352210.9	TSL:1	c.175C>T	p.Arg59Trp	missense	Exon 3 of 13	ENSP00000343943.5	P50336
	PPOX	ENST00000881040.1		c.175C>T	p.Arg59Trp	missense	Exon 3 of 14	ENSP00000551099.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Variegate porphyria (3)
1	-	-	not provided (1)
1	-	-	Variegate porphyria, childhood-onset (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.90		Loss of disorder (P = 0.025)
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918324; hg19: chr1-161136977; COSMIC: COSV57090035; COSMIC: COSV57090035;