rs1675534

Variant names:

• chr3-98582249-G-A
• rs1675534
• NM_000097.7:c.1173-738C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000097.7(CPOX):​c.1173-738C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 151,864 control chromosomes in the GnomAD database, including 7,322 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7322 hom., cov: 31)
• Consequence: CPOX NM_000097.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 3 publications found

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

ENSG00000285635 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.1173-738C>T		intron_variant	Intron 5 of 6	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1172+3192C>T		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1279+3192C>T		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.1173-738C>T		intron_variant	Intron 5 of 6		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.57-738C>T		intron_variant	Intron 1 of 3	5		ENSP00000425880.1
CPOX	ENST00000510489.1	n.423-738C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45745 AN: 151748 Hom.: 7325 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.285

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.301 AC: 45747 AN: 151864 Hom.: 7322 Cov.: 31 AF XY: 0.302 AC XY: 22412 AN XY: 74218

African (AFR) AF: 0.419 AC: 17336 AN: 41372

American (AMR) AF: 0.242 AC: 3691 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3466

East Asian (EAS) AF: 0.222 AC: 1148 AN: 5166

South Asian (SAS) AF: 0.148 AC: 713 AN: 4816

European-Finnish (FIN) AF: 0.359 AC: 3783 AN: 10524

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17565 AN: 67954

Other (OTH) AF: 0.282 AC: 594 AN: 2108

Alfa AF: 0.263 Hom.: 4118

Bravo AF: 0.297

Asia WGS AF: 0.185 AC: 641 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.7
DANN	Benign	0.61
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1675534; hg19: chr3-98301093;