rs121917868
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000097.7(CPOX):āc.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
NM_000097.7 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 7.67
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]
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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 |
---|---|---|---|---|---|---|---|---|
CPOX | NM_000097.7 | c.1210A>G | p.Lys404Glu | missense_variant | 6/7 | ENST00000647941.2 | NP_000088.3 | |
CPOX | XM_005247125.5 | c.1173-3204A>G | intron_variant | XP_005247182.1 | ||||
CPOX | XR_001740025.3 | n.1280-3204A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPOX | ENST00000647941.2 | c.1210A>G | p.Lys404Glu | missense_variant | 6/7 | NM_000097.7 | ENSP00000497326 | P1 | ||
CPOX | ENST00000510489.1 | n.460A>G | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251470Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135914
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GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461784Hom.: 0 Cov.: 30 AF XY: 0.0000564 AC XY: 41AN XY: 727190
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GnomAD4 genome AF: 0.0000789 AC: 12AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74336
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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 submitter | clinical testing | GeneDx | Jun 26, 2017 | The 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 submitter | clinical testing | Revvity Omics, Revvity | May 08, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2024 | This 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 provided | literature only | OMIM | Feb 15, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | The 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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 23, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Benign
D;.
Sift4G
Benign
T;.
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at