3-98580354-C-G

Variant names:

• chr3-98580354-C-G
• rs72924727
• NM_000097.7:c.*329G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000097.7(CPOX):​c.*329G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,012,022 control chromosomes in the GnomAD database, including 185 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 (117 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.15
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-98580354-C-G is Benign according to our data. Variant chr3-98580354-C-G is described in ClinVar as [Benign]. Clinvar id is 346964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0229 (3482/152172) while in subpopulation AFR AF = 0.0482 (1999/41516). AF 95% confidence interval is 0.0464. There are 68 homozygotes in GnomAd4. There are 1636 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.*329G>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1173-2084G>C		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1280-2084G>C		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.*329G>C		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.161+1053G>C		intron_variant	Intron 2 of 3	5		ENSP00000425880.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3483 AN: 152054 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00794

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0128 AC: 10996 AN: 859850 Hom.: 117 Cov.: 19 AF XY: 0.0129 AC XY: 5136 AN XY: 398966

African (AFR) AF: 0.0526 AC: 885 AN: 16820

American (AMR) AF: 0.0167 AC: 42 AN: 2520

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 127 AN: 6466

East Asian (EAS) AF: 0.0101 AC: 58 AN: 5736

South Asian (SAS) AF: 0.0222 AC: 400 AN: 18050

European-Finnish (FIN) AF: 0.00427 AC: 6 AN: 1406

Middle Eastern (MID) AF: 0.0277 AC: 48 AN: 1732

European-Non Finnish (NFE) AF: 0.0115 AC: 8937 AN: 777818

Other (OTH) AF: 0.0168 AC: 493 AN: 29302

GnomAD4 genome AF: 0.0229 AC: 3482 AN: 152172 Hom.: 68 Cov.: 33 AF XY: 0.0220 AC XY: 1636 AN XY: 74374

African (AFR) AF: 0.0482 AC: 1999 AN: 41516

American (AMR) AF: 0.0195 AC: 298 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.00772 AC: 40 AN: 5182

South Asian (SAS) AF: 0.0184 AC: 89 AN: 4830

European-Finnish (FIN) AF: 0.00794 AC: 84 AN: 10586

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 840 AN: 67986

Other (OTH) AF: 0.0308 AC: 65 AN: 2112

Alfa AF: 0.00700 Hom.: 3

Bravo AF: 0.0260

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary coproporphyria Benign:1

Jan 13, 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	-0.86
CADD	Benign	0.43
DANN	Benign	0.62
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs72924727; hg19: chr3-98299198;