chr1-161170467-A-C

Variant names:

• chr1-161170467-A-C
• rs28936676
• NM_001122764.3:c.1046A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001122764.3(PPOX):​c.1046A>C​(p.Asp349Ala) variant causes a missense change involving the alteration of a 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. D349D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPOX NM_001122764.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.23
• Publications: 4 publications found

Genes affected

PPOX (HGNC:9280): (protoporphyrinogen oxidase) This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. Mutations in this gene cause variegate porphyria, an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

PPOX Gene-Disease associations (from GenCC):

• variegate porphyria

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 1-161170467-A-C is Pathogenic according to our data. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-161170467-A-C is described in CliVar as Pathogenic. Clinvar id is 8698.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPOX	NM_001122764.3	c.1046A>C	p.Asp349Ala	missense_variant	Exon 10 of 13	ENST00000367999.9	NP_001116236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPOX	ENST00000367999.9	c.1046A>C	p.Asp349Ala	missense_variant	Exon 10 of 13	1	NM_001122764.3	ENSP00000356978.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Variegate porphyria, childhood-onset Pathogenic:1

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Benign	0.86
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		7.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.93		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.92
MPC		1.5
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28936676; hg19: chr1-161140257;