2-70274964-A-T

Variant names:

• chr2-70274964-A-T
• NM_016297.4:c.500A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016297.4(PCYOX1):​c.500A>T​(p.Tyr167Phe) 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCYOX1 NM_016297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

Genes affected

PCYOX1 (HGNC:20588): (prenylcysteine oxidase 1) Prenylcysteine is released during the degradation of prenylated proteins. PCYOX1 catalyzes the degradation of prenylcysteine to yield free cysteines and a hydrophobic isoprenoid product (Tschantz et al., 1999 [PubMed 10585463]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCYOX1	NM_016297.4	c.500A>T	p.Tyr167Phe	missense_variant	Exon 4 of 6	ENST00000433351.7	NP_057381.3
PCYOX1	XM_047444689.1	c.269A>T	p.Tyr90Phe	missense_variant	Exon 4 of 6		XP_047300645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCYOX1	ENST00000433351.7	c.500A>T	p.Tyr167Phe	missense_variant	Exon 4 of 6	1	NM_016297.4	ENSP00000387654.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1437112 Hom.: 1 Cov.: 27 AF XY: 0.00000279 AC XY: 2 AN XY: 716552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500A>T (p.Y167F) alteration is located in exon 4 (coding exon 4) of the PCYOX1 gene. This alteration results from a A to T substitution at nucleotide position 500, causing the tyrosine (Y) at amino acid position 167 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.5	.;.;M;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.74, 0.71
MutPred		0.90		.;.;Loss of catalytic residue at I166 (P = 0.0731);Loss of catalytic residue at I166 (P = 0.0731);.;
MVP		0.45
MPC		0.43
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-70502096;