NM_000097.7:c.*475T>A

Variant names:

• chr3-98580208-A-T
• rs72924726
• NM_000097.7:c.*475T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000097.7(CPOX):​c.*475T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 995,704 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (68 hom., cov: 33)
  • Exomes 𝑓: 0.013 (114 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.511
• Publications: 1 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• harderoporphyria

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp

ENSG00000285635 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-98580208-A-T is Benign according to our data. Variant chr3-98580208-A-T is described in ClinVar as Benign. ClinVar VariationId is 346961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0229 (3482/152316) while in subpopulation AFR AF = 0.048 (1996/41564). AF 95% confidence interval is 0.0463. There are 68 homozygotes in GnomAd4. There are 1638 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AR,SD,AD gene

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.*475T>A		3_prime_UTR	Exon 7 of 7	NP_000088.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPOX	ENST00000647941.2	MANE Select	c.*475T>A		3_prime_UTR	Exon 7 of 7	ENSP00000497326.1	P36551-1
	ENSG00000285635	ENST00000512905.6	TSL:5	n.161+1199T>A		intron	N/A	ENSP00000425880.1	H0YA22
	CPOX	ENST00000946176.1		c.*475T>A		3_prime_UTR	Exon 8 of 8	ENSP00000616235.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3483 AN: 152198 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0127 AC: 10688 AN: 843388 Hom.: 114 Cov.: 22 AF XY: 0.0127 AC XY: 4974 AN XY: 390244

African (AFR) AF: 0.0527 AC: 830 AN: 15764

American (AMR) AF: 0.0147 AC: 37 AN: 2522

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 102 AN: 5294

East Asian (EAS) AF: 0.00521 AC: 21 AN: 4030

South Asian (SAS) AF: 0.0215 AC: 388 AN: 18006

European-Finnish (FIN) AF: 0.00135 AC: 1 AN: 742

Middle Eastern (MID) AF: 0.0250 AC: 41 AN: 1642

European-Non Finnish (NFE) AF: 0.0115 AC: 8801 AN: 767460

Other (OTH) AF: 0.0167 AC: 467 AN: 27928

GnomAD4 genome AF: 0.0229 AC: 3482 AN: 152316 Hom.: 68 Cov.: 33 AF XY: 0.0220 AC XY: 1638 AN XY: 74480

African (AFR) AF: 0.0480 AC: 1996 AN: 41564

American (AMR) AF: 0.0197 AC: 301 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5186

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4828

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10620

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0123 AC: 838 AN: 68028

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0192 Hom.: 10

Bravo AF: 0.0260

Asia WGS AF: 0.0220 AC: 76 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary coproporphyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.47
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism

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: rs72924726; hg19: chr3-98299052;