3-98580004-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Benign (★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-98580004-C-T is Benign according to our data. Variant chr3-98580004-C-T is described in ClinVar as [Benign]. Clinvar id is 346956.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
CPOX	NM_000097.7	c.*679G>A		3_prime_UTR_variant	7/7	ENST00000647941.2
CPOX	XM_005247125.5	c.1173-1734G>A		intron_variant
CPOX	XR_001740025.3	n.1280-1734G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPOX	ENST00000647941.2	c.*679G>A		3_prime_UTR_variant	7/7		NM_000097.7	P1

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

Gnomad4 AFR exome AF: 0.0844

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0206

Gnomad4 EAS exome AF: 0.00552

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.00712

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0189

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

Gnomad4 AFR AF: 0.0753

Gnomad4 AMR AF: 0.0229

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00771

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0365

Alfa AF: 0.0232 Hom.: 28

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.5
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72924722; hg19: chr3-98298848;