1-42757782-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000296388.10(P3H1):c.1080+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.000126 in 1,614,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 0 hom. )
Consequence
P3H1
ENST00000296388.10 splice_donor
ENST00000296388.10 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.16
Genes affected
P3H1 (HGNC:19316): (prolyl 3-hydroxylase 1) This gene encodes an enzyme that is a member of the collagen prolyl hydroxylase family. These enzymes are localized to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Mutations in this gene are associated with osteogenesis imperfecta type VIII. Three alternatively spliced transcript variants encoding different isoforms have been described. Other variants may exist, but their biological validity has not been determined. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.4, offset of -5, new splice context is: cccGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-42757782-C-A is Pathogenic according to our data. Variant chr1-42757782-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
P3H1 | NM_022356.4 | c.1080+1G>T | splice_donor_variant | ENST00000296388.10 | NP_071751.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
P3H1 | ENST00000296388.10 | c.1080+1G>T | splice_donor_variant | 1 | NM_022356.4 | ENSP00000296388 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000591 AC: 90AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 251492Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135920
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GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50AN XY: 727246
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GnomAD4 genome AF: 0.000591 AC: 90AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74492
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 8 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 12, 2023 | PVS1, PS3, PM3_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change affects a donor splice site in intron 5 of the P3H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in P3H1 are known to be pathogenic (PMID: 17277775, 18566967, 19088120, 22281939). This variant is present in population databases (rs72659351, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with osteogenesis imperfecta (PMID: 17277775, 22281939, 27509835, 29150909). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 12, 2020 | The P3H1 c.1080+1G>T variant (rs72659351) is a West African founder mutation that has been described in the homozygous and compound heterozygous states in multiple individuals affected with osteogenesis imperfecta (Cabral 2007, Cabral 2012, Fratzl-Zelman 2016). It is reported as pathogenic in ClinVar (Variation ID: 1253) and observed in the African population at an overall frequency of 0.25% (59/24040 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice donor site of intron 5, and analysis of fibroblasts from affected patients carrying this variant demonstrated decreased transcript, absent P3H1 protein expression, and impaired collagen secretion (Cabral 2007). Based on available information, this variant is considered pathogenic. REFERENCES Cabral WA et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007 Mar;39(3):359-65. Cabral WA et al. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet Med. 2012 May;14(5):543-51. Fratzl-Zelman N et al. Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization. J Clin Endocrinol Metab. 2016 Sep;101(9):3516-25. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 06, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong, PP1 strong - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | P3H1: PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2022 | Common founder splice variant in individuals of West African ancestry (Cabral et al., 2012); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24498616, 27644073, 27509835, 29150909, 25525159, 17277775, 27383115, 26634552, 26525746, 30246063, 31085342, 31429852, 31589614, 32123938, 22281939) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 22, 2016 | - - |
Osteogenesis imperfecta Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 01, 2018 | - - |
P3H1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 18, 2024 | The P3H1 c.1080+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS5+1G>T in the literature. It is a founder variant in individuals of West African descent and has been reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive osteogenesis imperfecta (Cabral et al. 2007. PubMed ID: 17277775; Cabral et al. 2012. PubMed ID: 22281939; Fratzl-Zelman et al. 2016. PubMed ID: 27383115; Bardai et al. 2016. PubMed ID: 27509835; Santana et al. 2018. PubMed ID: 30246063; Trancozo et al. 2019. PubMed ID: 31429852). This variant is reported in 0.25% of alleles in individuals of African descent in gnomAD, which is consistent with this being a founder variant. Variants that disrupt the consensus splice donor site in P3H1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 6
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at