1-161166553-C-G

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.-128C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,391,242 control chromosomes in the GnomAD database, including 3,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (266 hom., cov: 33)
  • Exomes 𝑓: 0.071 (3553 hom.)
• Consequence: PPOX NM_001122764.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.851

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 1-161166553-C-G is Benign according to our data. Variant chr1-161166553-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 293244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPOX	NM_001122764.3	c.-128C>G		5_prime_UTR_variant	1/13	ENST00000367999.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPOX	ENST00000367999.9	c.-128C>G		5_prime_UTR_variant	1/13	1	NM_001122764.3	P1

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7632 AN: 152206 Hom.: 266 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0939

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0766

Gnomad OTH AF: 0.0487

GnomAD4 exome AF: 0.0708 AC: 87706 AN: 1238918 Hom.: 3553 Cov.: 32 AF XY: 0.0686 AC XY: 41064 AN XY: 598276

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.0347

Gnomad4 ASJ exome AF: 0.0385

Gnomad4 EAS exome AF: 0.0000963

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0873

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0584

GnomAD4 genome AF: 0.0501 AC: 7630 AN: 152324 Hom.: 266 Cov.: 33 AF XY: 0.0491 AC XY: 3654 AN XY: 74478

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0939

Gnomad4 NFE AF: 0.0766

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0617 Hom.: 42

Bravo AF: 0.0458

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Variegate porphyria Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	12
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs72714915; hg19: chr1-161136343; COSMIC: COSV57090960; COSMIC: COSV57090960;