rs72659351

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_022356.4(P3H1):​c.1080+1G>T variant causes a splice donor, intron 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
NM_022356.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 5.16
Variant links:
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]

Genome browser will be placed here

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 rank MANE Protein UniProt
P3H1NM_022356.4 linkc.1080+1G>T splice_donor_variant, intron_variant Intron 5 of 14 ENST00000296388.10 NP_071751.3 Q32P28-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
P3H1ENST00000296388.10 linkc.1080+1G>T splice_donor_variant, intron_variant Intron 5 of 14 1 NM_022356.4 ENSP00000296388.5 Q32P28-1

Frequencies

GnomAD3 genomes
AF:
0.000591
AC:
90
AN:
152222
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00207
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000207
AC:
52
AN:
251492
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00277
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000780
AC:
114
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.0000688
AC XY:
50
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00293
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000591
AC:
90
AN:
152340
Hom.:
0
Cov.:
32
AF XY:
0.000631
AC XY:
47
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00207
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000145
Hom.:
0
Bravo
AF:
0.000657
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000222
AC:
27
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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
Apr 06, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong, PP1 strong -

Mar 12, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 12, 2023
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PS3, PM3_Strong -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Apr 11, 2023
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Nov 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

P3H1: PVS1, PM2, PM3 -

Apr 12, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Sep 22, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Osteogenesis imperfecta Pathogenic:1
Oct 01, 2018
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

P3H1-related disorder Pathogenic:1
Jan 18, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.98
Position offset: 6
DS_DL_spliceai
1.0
Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72659351; hg19: chr1-43223453; API