3-98588852-T-G

Position:

chr3-98588852-T-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 346979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-98588852-T-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CPOX	NM_000097.7 linkuse as main transcript	c.814A>C	p.Asn272His	missense_variant, splice_region_variant	4/7	ENST00000647941.2	NP_000088.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2 linkuse as main transcript	c.814A>C	p.Asn272His	missense_variant, splice_region_variant	4/7		NM_000097.7	ENSP00000497326	P1	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

GnomAD3 exomes

AF:

0.168

AC:

42342

AN:

251336

Hom.:

4458

AF XY:

0.160

AC XY:

21731

AN XY:

135844

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 SAS exome

AF:

0.114

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

Gnomad4 AFR exome

AF:

0.459

Gnomad4 AMR exome

AF:

0.145

Gnomad4 ASJ exome

AF:

0.0796

Gnomad4 EAS exome

AF:

0.201

Gnomad4 SAS exome

AF:

0.114

Gnomad4 FIN exome

AF:

0.225

Gnomad4 NFE exome

AF:

0.133

Gnomad4 OTH exome

AF:

0.152

GnomAD4 genome

AF:

0.232

AC:

35306

AN:

152108

Hom.:

5521

Cov.:

AF XY:

0.234

AC XY:

17388

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.444

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.0794

Gnomad4 EAS

AF:

0.212

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.234

Gnomad4 NFE

AF:

0.140

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.150

Hom.:

3974

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

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Acute intermittent porphyria

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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

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

MutationTaster

Benign

0.42

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over