rs999497211

Variant names:

• chr1-161166672-G-A
• rs999497211
• NM_001122764.3:c.-9G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-161166672-G-A
• chr1-161166672-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_001122764.3(PPOX):​c.-9G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,501,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PPOX NM_001122764.3 splice_region
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.782
• Publications: 0 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, SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 1-161166672-G-A is Pathogenic according to our data. Variant chr1-161166672-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2202870.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122764.3. 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
	PPOX	NM_001122764.3	MANE Select	c.-9G>A		splice_region	Exon 1 of 13	NP_001116236.1	P50336
	PPOX	NM_001122764.3	MANE Select	c.-9G>A		5_prime_UTR	Exon 1 of 13	NP_001116236.1	P50336
	PPOX	NM_001350128.2		c.-9G>A		splice_region	Exon 1 of 12	NP_001337057.1	B4DY76

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	ENST00000367999.9	TSL:1 MANE Select	c.-9G>A		splice_region	Exon 1 of 13	ENSP00000356978.4	P50336
	PPOX	ENST00000367999.9	TSL:1 MANE Select	c.-9G>A		5_prime_UTR	Exon 1 of 13	ENSP00000356978.4	P50336
	PPOX	ENST00000352210.9	TSL:1	c.-9+61G>A		intron	N/A	ENSP00000343943.5	P50336

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000147

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000119 AC: 161 AN: 1349524 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 80 AN XY: 661780

African (AFR) AF: 0.00 AC: 0 AN: 30828

American (AMR) AF: 0.000332 AC: 11 AN: 33116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22670

East Asian (EAS) AF: 0.00 AC: 0 AN: 35378

South Asian (SAS) AF: 0.000190 AC: 14 AN: 73690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32842

Middle Eastern (MID) AF: 0.00103 AC: 4 AN: 3896

European-Non Finnish (NFE) AF: 0.000118 AC: 125 AN: 1060888

Other (OTH) AF: 0.000125 AC: 7 AN: 56216

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	21
DANN	Benign	0.91
PhyloP100		0.78
PromoterAI		-0.098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=21/279	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs999497211; hg19: chr1-161136462;