3-98580488-A-G

Variant names:

• chr3-98580488-A-G
• rs139248891
• NM_000097.7:c.*195T>C

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.*195T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,428,378 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0880
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-98580488-A-G is Benign according to our data. Variant chr3-98580488-A-G is described in ClinVar as [Benign]. Clinvar id is 899847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (296/152348) while in subpopulation AFR AF = 0.00659 (274/41584). AF 95% confidence interval is 0.00595. There are 1 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.*195T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1173-2218T>C		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1280-2218T>C		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.*195T>C		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.161+919T>C		intron_variant	Intron 2 of 3	5		ENSP00000425880.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152230 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00661

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000185 AC: 236 AN: 1276030 Hom.: 2 Cov.: 30 AF XY: 0.000161 AC XY: 100 AN XY: 620050

African (AFR) AF: 0.00702 AC: 198 AN: 28198

American (AMR) AF: 0.000618 AC: 13 AN: 21034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19060

East Asian (EAS) AF: 0.00 AC: 0 AN: 33374

South Asian (SAS) AF: 0.00 AC: 0 AN: 64066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3584

European-Non Finnish (NFE) AF: 0.00000293 AC: 3 AN: 1025172

Other (OTH) AF: 0.000418 AC: 22 AN: 52654

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152348 Hom.: 1 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74498

African (AFR) AF: 0.00659 AC: 274 AN: 41584

American (AMR) AF: 0.00124 AC: 19 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.00216

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary coproporphyria Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.86
DANN	Benign	0.44
PhyloP100		0.088
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs139248891; hg19: chr3-98299332;