chr3-98588852-T-C

Variant names:

• chr3-98588852-T-C
• rs1131857
• NM_000097.7:c.814A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000097.7(CPOX):​c.814A>G​(p.Asn272Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N272H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPOX NM_000097.7 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 44 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17135116).

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.814A>G	p.Asn272Asp	missense splice_region	Exon 4 of 7	NP_000088.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPOX	ENST00000647941.2	MANE Select	c.814A>G	p.Asn272Asp	missense splice_region	Exon 4 of 7	ENSP00000497326.1
	CPOX	ENST00000946176.1		c.901A>G	p.Asn301Asp	missense splice_region	Exon 5 of 8	ENSP00000616235.1
	CPOX	ENST00000932270.1		c.811A>G	p.Asn271Asp	missense splice_region	Exon 4 of 7	ENSP00000602329.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.33	N
PhyloP100		1.8
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.28
Sift	Benign	0.46	T
Sift4G	Benign	0.68	T
Polyphen		0.038	B
Vest4		0.18
MutPred		0.34		Loss of glycosylation at K273 (P = 0.0714)
MVP		0.78
MPC		0.62
ClinPred		0.33	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.43
Mutation Taster		=89/11	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: rs1131857; hg19: chr3-98307696;