1-161171095-T-G

Variant names:

• chr1-161171095-T-G
• rs148292941
• NM_001122764.3:c.1353T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001122764.3(PPOX):​c.1353T>G​(p.Tyr451*) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y451Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPOX NM_001122764.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.356
• 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]

B4GALT3 (HGNC:926): (beta-1,4-galactosyltransferase 3) This gene is one of seven beta-1,4-galactosyltransferase (beta4GalT) genes. They encode type II membrane-bound glycoproteins that appear to have exclusive specificity for the donor substrate UDP-galactose; all transfer galactose in a beta1,4 linkage to similar acceptor sugars: GlcNAc, Glc, and Xyl. Each beta4GalT has a distinct function in the biosynthesis of different glycoconjugates and saccharide structures. As type II membrane proteins, they have an N-terminal hydrophobic signal sequence that directs the protein to the Golgi apparatus and which then remains uncleaved to function as a transmembrane anchor. By sequence similarity, the beta4GalTs form four groups: beta4GalT1 and beta4GalT2, beta4GalT3 and beta4GalT4, beta4GalT5 and beta4GalT6, and beta4GalT7. This gene encodes an enzyme that may be mainly involved in the synthesis of the first N-acetyllactosamine unit of poly-N-acetyllactosamine chains. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0565 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161171095-T-G is Pathogenic according to our data. Variant chr1-161171095-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 523355.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	NM_001122764.3	MANE Select	c.1353T>G	p.Tyr451*	stop_gained	Exon 13 of 13	NP_001116236.1
	PPOX	NM_000309.5		c.1353T>G	p.Tyr451*	stop_gained	Exon 13 of 13	NP_000300.1
	PPOX	NM_001365398.1		c.1353T>G	p.Tyr451*	stop_gained	Exon 13 of 13	NP_001352327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPOX	ENST00000367999.9	TSL:1 MANE Select	c.1353T>G	p.Tyr451*	stop_gained	Exon 13 of 13	ENSP00000356978.4
	PPOX	ENST00000352210.9	TSL:1	c.1353T>G	p.Tyr451*	stop_gained	Exon 13 of 13	ENSP00000343943.5
	PPOX	ENST00000652182.1		c.1242T>G	p.Tyr414*	stop_gained	Exon 12 of 12	ENSP00000498884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Constipation;C0149931:Migraine;C0522153:Abnormal urinary color;C2132198:Abnormal blistering of the skin Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.61	D
PhyloP100		-0.36
Vest4		0.88
ClinPred		1.0	D
GERP RS		0.080
Mutation Taster		=7/193	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: rs148292941; hg19: chr1-161140885;