rs724160006
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_018192.4(P3H2):c.556C>T(p.Gln186Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
P3H2
NM_018192.4 stop_gained
NM_018192.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.73
Genes affected
P3H2 (HGNC:19317): (prolyl 3-hydroxylase 2) This gene encodes a member of the prolyl 3-hydroxylase subfamily of 2-oxo-glutarate-dependent dioxygenases. These enzymes play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. Mutations in this gene are associated with nonsyndromic severe myopia with cataract and vitreoretinal degeneration, and downregulation of this gene may play a role in breast cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-189995367-G-A is Pathogenic according to our data. Variant chr3-189995367-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 162462.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
P3H2 | NM_018192.4 | c.556C>T | p.Gln186Ter | stop_gained | 2/15 | ENST00000319332.10 | |
P3H2 | NM_001134418.2 | c.13C>T | p.Gln5Ter | stop_gained | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
P3H2 | ENST00000319332.10 | c.556C>T | p.Gln186Ter | stop_gained | 2/15 | 1 | NM_018192.4 | P1 | |
P3H2 | ENST00000427335.6 | c.13C>T | p.Gln5Ter | stop_gained | 2/15 | 1 | |||
P3H2 | ENST00000444866.5 | c.13C>T | p.Gln5Ter | stop_gained | 2/4 | 4 | |||
P3H2 | ENST00000426003.1 | c.13C>T | p.Gln5Ter | stop_gained | 2/4 | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727210
GnomAD4 exome
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1
AN:
1461814
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31
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0
AN XY:
727210
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myopia, high, with cataract and vitreoretinal degeneration Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2023 | This premature translational stop signal has been observed in individual(s) with high myopia with early-onset cataract (PMID: 24172257). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 162462). This variant is also known as LEPREL1 c.13C>T (p.Q5X). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln186*) in the P3H2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in P3H2 are known to be pathogenic (PMID: 24172257, 25469533). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at