3-98580343-T-C

Variant names:

• chr3-98580343-T-C
• rs886058945
• NM_000097.7:c.*340A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000097.7(CPOX):​c.*340A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,007,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.492
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000164 (25/152288) while in subpopulation NFE AF = 0.000324 (22/68004). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.*340A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1173-2073A>G		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1280-2073A>G		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.*340A>G		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.161+1064A>G		intron_variant	Intron 2 of 3	5		ENSP00000425880.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 147 AN: 855422 Hom.: 0 Cov.: 20 AF XY: 0.000179 AC XY: 71 AN XY: 396526

African (AFR) AF: 0.000181 AC: 3 AN: 16572

American (AMR) AF: 0.00 AC: 0 AN: 2570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6080

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 18216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1698

European-Non Finnish (NFE) AF: 0.000181 AC: 140 AN: 775020

Other (OTH) AF: 0.000139 AC: 4 AN: 28876

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74450

African (AFR) AF: 0.0000721 AC: 3 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000147

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary coproporphyria Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.47
PhyloP100		-0.49

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: rs886058945; hg19: chr3-98299187;