3-98580004-C-T

Variant names:

• chr3-98580004-C-T
• rs72924722
• NM_000097.7:c.*679G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000097.7(CPOX):​c.*679G>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 0.0161 in 984,934 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.031 (133 hom., cov: 33)
  • Exomes 𝑓: 0.013 (144 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.290
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• CPOX-related hereditary coproporphyria

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary coproporphyria

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• harderoporphyria

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp

ENSG00000285635 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.*679G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1173-1734G>A		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1280-1734G>A		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.*679G>A		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.161+1403G>A		intron_variant	Intron 2 of 3	5		ENSP00000425880.1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4664 AN: 152104 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0369

GnomAD4 exome AF: 0.0135 AC: 11205 AN: 832712 Hom.: 144 Cov.: 25 AF XY: 0.0134 AC XY: 5159 AN XY: 384618

African (AFR) AF: 0.0844 AC: 1330 AN: 15750

American (AMR) AF: 0.0163 AC: 16 AN: 980

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 106 AN: 5140

East Asian (EAS) AF: 0.00552 AC: 20 AN: 3622

South Asian (SAS) AF: 0.0224 AC: 368 AN: 16442

European-Finnish (FIN) AF: 0.00712 AC: 5 AN: 702

Middle Eastern (MID) AF: 0.0272 AC: 44 AN: 1620

European-Non Finnish (NFE) AF: 0.0116 AC: 8801 AN: 761180

Other (OTH) AF: 0.0189 AC: 515 AN: 27276

GnomAD4 genome AF: 0.0308 AC: 4687 AN: 152222 Hom.: 133 Cov.: 33 AF XY: 0.0298 AC XY: 2222 AN XY: 74448

African (AFR) AF: 0.0753 AC: 3126 AN: 41518

American (AMR) AF: 0.0229 AC: 351 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3466

East Asian (EAS) AF: 0.00771 AC: 40 AN: 5188

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4832

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 850 AN: 67990

Other (OTH) AF: 0.0365 AC: 77 AN: 2108

Alfa AF: 0.0223 Hom.: 49

Bravo AF: 0.0342

Asia WGS AF: 0.0260 AC: 90 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary coproporphyria Benign:1

Jan 12, 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	-0.77
CADD	Benign	2.5
DANN	Benign	0.66
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs72924722; hg19: chr3-98298848;