rs121917871

Variant names:

• chr3-98593420-G-A
• rs121917871
• NM_000097.7:c.85C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-98593420-G-A
• chr3-98593420-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000097.7(CPOX):​c.85C>T​(p.Gln29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q29Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPOX NM_000097.7 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.38
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-98593420-G-A is Pathogenic according to our data. Variant chr3-98593420-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 458.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPOX	NM_000097.7	c.85C>T	p.Gln29*	stop_gained	Exon 1 of 7	ENST00000647941.2	NP_000088.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPOX	ENST00000647941.2	c.85C>T	p.Gln29*	stop_gained	Exon 1 of 7		NM_000097.7	ENSP00000497326.1
CPOX	ENST00000513674.1	n.85C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000424924.1
CPOX	ENST00000515041.1	n.191C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1307024 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 644152

African (AFR) AF: 0.00 AC: 0 AN: 25982

American (AMR) AF: 0.00 AC: 0 AN: 23036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22384

East Asian (EAS) AF: 0.00 AC: 0 AN: 28978

South Asian (SAS) AF: 0.00 AC: 0 AN: 70654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3850

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045442

Other (OTH) AF: 0.00 AC: 0 AN: 54188

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Coproporphyria Pathogenic:1

Nov 16, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	0.025
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.063	N
PhyloP100		1.4
Vest4		0.46
GERP RS		0.48
PromoterAI		0.088	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Mutation Taster		=5/195	disease causing (ClinVar)

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: rs121917871; hg19: chr3-98312264;