Genetic Variant CPOX:c.*595C>A (chr3-98580088-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_000097.7(CPOX):c.*595C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 920,612 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 Benign (★).

Frequency

Genomes: 𝑓 0.0041 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CPOX
NM_000097.7 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.225

Variant links:

Genes affected

CPOX (HGNC:2321): (coproporphyrinogen oxidase) The protein encoded by this gene is the sixth enzyme of the heme biosynthetic pathway. The encoded enzyme is soluble and found in the intermembrane space of mitochondria. This enzyme catalyzes the stepwise oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX, a precursor of heme. Defects in this gene are a cause of hereditary coproporphyria (HCP).[provided by RefSeq, Oct 2009]

CPOX links:

ENSG00000285635 (HGNC:):

ENSG00000285635 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 3-98580088-G-T is Benign according to our data. Variant chr3-98580088-G-T is described in ClinVar as [Benign]. Clinvar id is 903461.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00408 (380/93118) while in subpopulation AFR AF= 0.0189 (368/19470). AF 95% confidence interval is 0.0173. There are 0 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7 link	c.*595C>A	3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3	P36551-1
CPOX	XM_005247125.5 link	c.1173-1818C>A	intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3 link	n.1280-1818C>A	intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941 link	c.*595C>A		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1		P36551-1
ENSG00000285635	ENST00000512905.6 link	n.161+1319C>A		intron_variant	Intron 2 of 3	5		ENSP00000425880.1		H0YA22

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

376

AN:

93040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000700

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:

0.0000430

Gnomad OTH

AF:

0.00238

GnomAD4 exome

AF:

0.000224

AC:

185

AN:

827494

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

AN XY:

382480

show subpopulations

Gnomad4 AFR exome

AF:

0.0109

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000132

Gnomad4 OTH exome

AF:

0.000517

GnomAD4 genome

AF:

0.00408

AC:

380

AN:

93118

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

161

AN XY:

45066

show subpopulations

Gnomad4 AFR

AF:

0.0189

Gnomad4 AMR

AF:

0.000698

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000430

Gnomad4 OTH

AF:

0.00233

Alfa

AF:

0.00173

Hom.:

Bravo

AF:

0.00277

Asia WGS

AF:

0.000290

AC:

AN:

3460

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary coproporphyria

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.95

DANN

Benign

0.54

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

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