chr3-98588852-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000097.7(CPOX):c.814A>C(p.Asn272His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,584 control chromosomes in the GnomAD database, including 23,301 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5521 hom., cov: 33)

Exomes 𝑓: 0.14 ( 17780 hom. )

Consequence

CPOX
NM_000097.7 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 1.84

Publications

44 publications found

Variant links:

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

CPOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036540926).

BP6

Variant 3-98588852-T-G is Benign according to our data. Variant chr3-98588852-T-G is described in ClinVar as Benign. ClinVar VariationId is 346979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7 link	c.814A>C	p.Asn272His	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000647941.2	NP_000088.3	P36551-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2 link	c.814A>C	p.Asn272His	missense_variant, splice_region_variant	Exon 4 of 7		NM_000097.7	ENSP00000497326.1		P36551-1

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35284

AN:

151990

Hom.:

5518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.444

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.0794

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.202

GnomAD2 exomes

AF:

0.168

AC:

42342

AN:

251336

AF XY:

0.160

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.0787

Gnomad EAS exome

AF:

0.226

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.144

AC:

210957

AN:

1461476

Hom.:

17780

Cov.:

AF XY:

0.143

AC XY:

103627

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.459

AC:

15345

AN:

33466

American (AMR)

AF:

0.145

AC:

6476

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0796

AC:

2079

AN:

26128

East Asian (EAS)

AF:

0.201

AC:

7972

AN:

39696

South Asian (SAS)

AF:

0.114

AC:

9789

AN:

86244

European-Finnish (FIN)

AF:

0.225

AC:

12013

AN:

53412

Middle Eastern (MID)

AF:

0.108

AC:

622

AN:

5766

European-Non Finnish (NFE)

AF:

0.133

AC:

147472

AN:

1111682

Other (OTH)

AF:

0.152

AC:

9189

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

8862

17723

26585

35446

44308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5410

10820

16230

21640

27050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.232

AC:

35306

AN:

152108

Hom.:

5521

Cov.:

AF XY:

0.234

AC XY:

17388

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.444

AC:

18388

AN:

41446

American (AMR)

AF:

0.163

AC:

2494

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0794

AC:

275

AN:

3464

East Asian (EAS)

AF:

0.212

AC:

1099

AN:

5184

South Asian (SAS)

AF:

0.105

AC:

508

AN:

4822

European-Finnish (FIN)

AF:

0.234

AC:

2479

AN:

10574

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9503

AN:

68002

Other (OTH)

AF:

0.200

AC:

422

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1244

2487

3731

4974

6218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

350

700

1050

1400

1750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.163

Hom.:

10176

Bravo

AF:

0.237

TwinsUK

AF:

0.136

AC:

505

ALSPAC

AF:

0.125

AC:

481

ESP6500AA

AF:

0.445

AC:

1959

ESP6500EA

AF:

0.133

AC:

1141

ExAC

AF:

0.174

AC:

21129

Asia WGS

AF:

0.162

AC:

562

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.127

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary coproporphyria

Benign:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Acute intermittent porphyria

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

0.0091

Eigen_PC

Benign

0.084

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;.

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.6

L;L

PhyloP100

1.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.060

T;.

Sift4G

Benign

0.10

T;.

Polyphen

0.76

P;P

Vest4

0.068

MPC

0.92

ClinPred

0.017

GERP RS

4.8

Varity_R

0.12

gMVP

0.45

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over