rs121917868

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000097.7(CPOX):ā€‹c.1210A>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.000063 ( 0 hom. )

Consequence

CPOX
NM_000097.7 missense

Scores

12
4
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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 [Likely_pathogenic]. Clinvar id is 453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CPOXNM_000097.7 linkuse as main transcriptc.1210A>G p.Lys404Glu missense_variant 6/7 ENST00000647941.2 NP_000088.3
CPOXXM_005247125.5 linkuse as main transcriptc.1173-3204A>G intron_variant XP_005247182.1
CPOXXR_001740025.3 linkuse as main transcriptn.1280-3204A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CPOXENST00000647941.2 linkuse as main transcriptc.1210A>G p.Lys404Glu missense_variant 6/7 NM_000097.7 ENSP00000497326 P1P36551-1
CPOXENST00000510489.1 linkuse as main transcriptn.460A>G non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152160
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251470
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135914
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 SAS 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:
92
AN:
1461784
Hom.:
0
Cov.:
30
AF XY:
0.0000564
AC XY:
41
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000347
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 26, 2017The K404E variant in the CPOX gene has been reported previously along with another variant in an individual with harderoporphyria with severe hemolytic anemia with splenomegaly and compensatory hyperactive bone marrow. Carrier parents and sister were clinically unaffected but showed a decrease in CPOX activity (Lamoril et al., 1998). The K404E variant, also referred to as K304E using alternate nomenclature, was also reported in three siblings with harderoporphyria. The variant was assumed to be homozygous due to absence of the normal allele and decreased CPOX enzyme activity in the affected siblings, and the heterozygous state of the father along with parental enzyme studies demonstrating heterozygosity for the same enzymatic defect in both parents. DNA was not obtained from the mother (Lamoril et al., 1995). In functional studies, the K404E mutant enzyme exhibits reduced enzyme activity compared to wild type enzyme (Kim et al., 2013; Lamoril et al., 1995). The K404E variant is observed in 4/66724 (0.006%) alleles in the ExAC dataset, and no homozygous individuals were reported (Lek et al., 2016). The K404E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret K404E as a likely pathogenic variant. -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 08, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 07, 2024This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 404 of the CPOX protein (p.Lys404Glu). This variant is present in population databases (rs121917868, gnomAD 0.009%). This missense change has been observed in individual(s) with harderoporphyria (PMID: 7757079, 9454777, 16159891). It has also been observed to segregate with disease in related individuals. This variant is also known as K304E. ClinVar contains an entry for this variant (Variation ID: 453). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CPOX protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CPOX function (PMID: 16159891, 24078084). For these reasons, this variant has been classified as Pathogenic. -
Harderoporphyria Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 15, 1998- -
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 25, 2023The heterozygous p.Lys404Glu variant in CPOX was identified by our study in one individual with harderoporphyria. The p.Lys404Glu variant in CPOX has been previously reported in three unrelated individuals with harderoporphyria (PMID: 16159891, PMID: 9454777, PMID: 7757079) and segregated with disease in three affected individuals from one family (PMID: 7757079), but has been identified in 0.008% (2/24962) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121917868). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 453) and was interpreted as pathogenic by Invitae and OMIM and as likely pathogenic by GeneDx and PerkinElmer Genomics. Of the three affected individuals previously reported (PMID: 16159891, PMID: 9454777, PMID: 7757079), two were homozygotes (PMID: 16159891, PMID: 7757079) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 9454777, ClinVar Variation ID: 457), which increases the likelihood that the p.Lys404Glu variant is pathogenic. In vitro functional studies provide some evidence that the p.Lys404Glu variant may slightly impact protein function (PMID: 24078084, PMID: 16159891, PMID: 7757079). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive harderoporphyria. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PS3_Supporting, PP1, PP3 (Richards 2015). -
Hereditary coproporphyria;C0342859:Harderoporphyria Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 23, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;.
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.9
D;.
REVEL
Pathogenic
0.94
Sift
Benign
0.033
D;.
Sift4G
Benign
0.090
T;.
Polyphen
1.0
D;D
Vest4
0.96
MVP
0.98
MPC
1.7
ClinPred
0.95
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121917868; hg19: chr3-98300318; API