1-161166434-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001122764.3(PPOX):c.-247C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,178,942 control chromosomes in the GnomAD database, including 82,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9530 hom., cov: 33)
  • Exomes 𝑓: 0.38 (72888 hom.)
• Consequence: PPOX NM_001122764.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-161166434-C-A is Benign according to our data. Variant chr1-161166434-C-A is described in ClinVar as [Benign]. Clinvar id is 293238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPOX	NM_001122764.3	c.-247C>A		5_prime_UTR_variant	1/13	ENST00000367999.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPOX	ENST00000367999.9	c.-247C>A		5_prime_UTR_variant	1/13	1	NM_001122764.3	P1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53311 AN: 152014 Hom.: 9509 Cov.: 33

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.376 AC: 386126 AN: 1026810 Hom.: 72888 Cov.: 32 AF XY: 0.375 AC XY: 183025 AN XY: 488254

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.360

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.358

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.351 AC: 53382 AN: 152132 Hom.: 9530 Cov.: 33 AF XY: 0.350 AC XY: 26043 AN XY: 74358

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.351

Alfa AF: 0.380 Hom.: 10634

Bravo AF: 0.353

Asia WGS AF: 0.404 AC: 1402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Variegate porphyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.77
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2301286; hg19: chr1-161136224;