3-98579756-C-T

Variant names:

• chr3-98579756-C-T
• rs7103
• NM_000097.7:c.*927G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000097.7(CPOX):​c.*927G>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 0.352 in 984,446 control chromosomes in the GnomAD database, including 62,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8104 hom., cov: 34)
  • Exomes 𝑓: 0.36 (54027 hom.)
• Consequence: CPOX NM_000097.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.334
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-98579756-C-T is Benign according to our data. Variant chr3-98579756-C-T is described in ClinVar as [Benign]. Clinvar id is 346955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.*927G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5	c.1173-1486G>A		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3	n.1280-1486G>A		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.*927G>A		3_prime_UTR_variant	Exon 7 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6	n.161+1651G>A		intron_variant	Intron 2 of 3	5		ENSP00000425880.1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47923 AN: 151978 Hom.: 8100 Cov.: 34

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.359 AC: 298738 AN: 832350 Hom.: 54027 Cov.: 25 AF XY: 0.360 AC XY: 138363 AN XY: 384462

African (AFR) AF: 0.168 AC: 2643 AN: 15770

American (AMR) AF: 0.350 AC: 344 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 2373 AN: 5142

East Asian (EAS) AF: 0.411 AC: 1486 AN: 3616

South Asian (SAS) AF: 0.397 AC: 6529 AN: 16440

European-Finnish (FIN) AF: 0.351 AC: 214 AN: 610

Middle Eastern (MID) AF: 0.434 AC: 703 AN: 1618

European-Non Finnish (NFE) AF: 0.361 AC: 274596 AN: 760890

Other (OTH) AF: 0.361 AC: 9850 AN: 27280

GnomAD4 genome AF: 0.315 AC: 47948 AN: 152096 Hom.: 8104 Cov.: 34 AF XY: 0.317 AC XY: 23602 AN XY: 74364

African (AFR) AF: 0.187 AC: 7777 AN: 41504

American (AMR) AF: 0.319 AC: 4880 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1626 AN: 3472

East Asian (EAS) AF: 0.388 AC: 2006 AN: 5172

South Asian (SAS) AF: 0.407 AC: 1961 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3837 AN: 10560

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24743 AN: 67960

Other (OTH) AF: 0.329 AC: 696 AN: 2114

Alfa AF: 0.353 Hom.: 26661

Bravo AF: 0.311

Asia WGS AF: 0.375 AC: 1307 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.88
CADD	Benign	0.64
DANN	Benign	0.58
PhyloP100		-0.33
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: rs7103; hg19: chr3-98298600;