1-161166530-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001122764.3(PPOX):c.-151G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,363,058 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 33)
  • Exomes 𝑓: 0.019 (252 hom.)
• Consequence: PPOX NM_001122764.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.288

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-161166530-G-T is Benign according to our data. Variant chr1-161166530-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 293242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2278/152346) while in subpopulation NFE AF= 0.0211 (1437/68022). AF 95% confidence interval is 0.0202. There are 27 homozygotes in gnomad4. There are 1187 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPOX	NM_001122764.3	c.-151G>T		5_prime_UTR_variant	1/13	ENST00000367999.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPOX	ENST00000367999.9	c.-151G>T		5_prime_UTR_variant	1/13	1	NM_001122764.3	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2279 AN: 152228 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0191 AC: 23073 AN: 1210712 Hom.: 252 Cov.: 32 AF XY: 0.0185 AC XY: 10824 AN XY: 583792

Gnomad4 AFR exome AF: 0.00243

Gnomad4 AMR exome AF: 0.00488

Gnomad4 ASJ exome AF: 0.00508

Gnomad4 EAS exome AF: 0.0000352

Gnomad4 SAS exome AF: 0.00388

Gnomad4 FIN exome AF: 0.0472

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0150 AC: 2278 AN: 152346 Hom.: 27 Cov.: 33 AF XY: 0.0159 AC XY: 1187 AN XY: 74492

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00897 Hom.: 1

Bravo AF: 0.0116

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Variegate porphyria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.6
Dann	Benign	0.52

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: rs115158839; hg19: chr1-161136320;