3-98580208-A-T

Variant names:

• chr3-98580208-A-T
• rs72924726
• NM_000097.7:c.*475T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000097.7(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (68 hom., cov: 33)
  • Exomes 𝑓: 0.013 (114 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.511
• Publications: 1 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=-0.84).
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AR,SD,AD 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	ENST00000647941.2	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

African (AFR) AF: 0.0527 AC: 830 AN: 15764

American (AMR) AF: 0.0147 AC: 37 AN: 2522

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 102 AN: 5294

East Asian (EAS) AF: 0.00521 AC: 21 AN: 4030

South Asian (SAS) AF: 0.0215 AC: 388 AN: 18006

European-Finnish (FIN) AF: 0.00135 AC: 1 AN: 742

Middle Eastern (MID) AF: 0.0250 AC: 41 AN: 1642

European-Non Finnish (NFE) AF: 0.0115 AC: 8801 AN: 767460

Other (OTH) AF: 0.0167 AC: 467 AN: 27928

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

African (AFR) AF: 0.0480 AC: 1996 AN: 41564

American (AMR) AF: 0.0197 AC: 301 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5186

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4828

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10620

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0123 AC: 838 AN: 68028

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

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
PhyloP100		0.51
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: rs72924726; hg19: chr3-98299052;