3-98579756-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.*927G>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 0.352 in 984,446 control chromosomes in the GnomAD database, including 62,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8104 hom., cov: 34)
  • Exomes 𝑓: 0.36 (54027 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.334

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=-0.88).
• BP6: Variant 3-98579756-C-T is Benign according to our data. Variant chr3-98579756-C-T is described in ClinVar as [Benign]. Clinvar id is 346955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPOX	NM_000097.7	c.*927G>A		3_prime_UTR_variant	7/7	ENST00000647941.2
CPOX	XM_005247125.5	c.1173-1486G>A		intron_variant
CPOX	XR_001740025.3	n.1280-1486G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPOX	ENST00000647941.2	c.*927G>A		3_prime_UTR_variant	7/7		NM_000097.7	P1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47923 AN: 151978 Hom.: 8100 Cov.: 34

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.359 AC: 298738 AN: 832350 Hom.: 54027 Cov.: 25 AF XY: 0.360 AC XY: 138363 AN XY: 384462

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.361

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.315 AC: 47948 AN: 152096 Hom.: 8104 Cov.: 34 AF XY: 0.317 AC XY: 23602 AN XY: 74364

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.329

Alfa AF: 0.358 Hom.: 10577

Bravo AF: 0.311

Asia WGS AF: 0.375 AC: 1307 AN: 3478

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 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 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	-0.88
Cadd	Benign	0.64
Dann	Benign	0.58

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: rs7103; hg19: chr3-98298600;