chr3-98581474-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000097.7(CPOX):c.1210A>G(p.Lys404Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CPOX
NM_000097.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.67

Publications

17 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
harderoporphyria
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp
hereditary coproporphyria
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

CPOX links:

ENSG00000285635 (HGNC:):

ENSG00000285635 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 3-98581474-T-C is Pathogenic according to our data. Variant chr3-98581474-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000097.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPOX	NM_000097.7	MANE Select	c.1210A>G	p.Lys404Glu	missense	Exon 6 of 7	NP_000088.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPOX	ENST00000647941.2	MANE Select	c.1210A>G	p.Lys404Glu	missense	Exon 6 of 7	ENSP00000497326.1	P36551-1
ENSG00000285635	ENST00000512905.6	TSL:5	n.94A>G		non_coding_transcript_exon	Exon 2 of 4	ENSP00000425880.1	H0YA22
CPOX	ENST00000946176.1		c.1297A>G	p.Lys433Glu	missense	Exon 7 of 8	ENSP00000616235.1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251470

AF XY:

0.0000441

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

1111932

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000789

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000224

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Harderoporphyria (2)

CPOX-related hereditary coproporphyria (1)

Hereditary coproporphyria;C0342859:Harderoporphyria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

7.7

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.94

Sift

Benign

0.033

Sift4G

Benign

0.090

Polyphen

1.0

Vest4

0.96

MVP

0.98

MPC

1.7

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.81

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over