ENST00000647941:c.*475T>A

Variant names:

• chr3-98580208-A-T
• rs72924726
• ENST00000647941:c.*475T>A

Variant summary

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

The ENST00000647941(CPOX):​c.*475T>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 0.0142 in 995,704 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (68 hom., cov: 33)
  • Exomes 𝑓: 0.013 (114 hom.)
• Consequence: CPOX ENST00000647941 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.511

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]

ENSG00000285635 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-98580208-A-T is Benign according to our data. Variant chr3-98580208-A-T is described in ClinVar as [Benign]. Clinvar id is 346961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0229 (3482/152316) while in subpopulation AFR AF= 0.048 (1996/41564). AF 95% confidence interval is 0.0463. There are 68 homozygotes in gnomad4. There are 1638 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 68 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.*475T>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1173-1938T>A		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1280-1938T>A		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941	c.*475T>A		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.161+1199T>A		intron_variant	Intron 2 of 3	5		ENSP00000425880.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3483 AN: 152198 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0127 AC: 10688 AN: 843388 Hom.: 114 Cov.: 22 AF XY: 0.0127 AC XY: 4974 AN XY: 390244

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.00521

Gnomad4 SAS exome AF: 0.0215

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0229 AC: 3482 AN: 152316 Hom.: 68 Cov.: 33 AF XY: 0.0220 AC XY: 1638 AN XY: 74480

Gnomad4 AFR AF: 0.0480

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0192 Hom.: 10

Bravo AF: 0.0260

Asia WGS AF: 0.0220 AC: 76 AN: 3470

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	-0.84
CADD	Benign	2.8
DANN	Benign	0.47

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: rs72924726; hg19: chr3-98299052;