Variant 1-161166672-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001122764.3(PPOX):c.-9G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,501,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PPOX
NM_001122764.3 splice_region

Scores

Splicing: ADA: 0.9955

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.782

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-161166672-G-A is Pathogenic according to our data. Variant chr1-161166672-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2202870.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPOX	NM_001122764.3 link	c.-9G>A		splice_region_variant	Exon 1 of 13	ENST00000367999.9	NP_001116236.1	P50336
PPOX	NM_001122764.3 link	c.-9G>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000367999.9	NP_001116236.1	P50336

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPOX	ENST00000367999.9 link	c.-9G>A		splice_region_variant	Exon 1 of 13	1	NM_001122764.3	ENSP00000356978.4		P50336
PPOX	ENST00000367999 link	c.-9G>A		5_prime_UTR_variant	Exon 1 of 13	1	NM_001122764.3	ENSP00000356978.4		P50336

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.000119

AC:

161

AN:

1349524

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

661780

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000332

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000190

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000118

Gnomad4 OTH exome

AF:

0.000125

GnomAD4 genome

AF:

0.000112

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000178

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the PPOX gene. It does not change the encoded amino acid sequence of the PPOX protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individuals with clinical features of variegate porphyria (PMID: 27667166). This variant is also known as c.1-176G>A. ClinVar contains an entry for this variant (Variation ID: 2202870). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.71

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: -4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over