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
Consequence
NM_022356.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000591 AC: 90AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000207 AC: 52AN: 251492Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135920
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50AN XY: 727246
GnomAD4 genome AF: 0.000591 AC: 90AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74492
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type 8 Pathogenic:7
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong, PP1 strong -
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. -
PVS1, PS3, PM3_Strong -
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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. -
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not provided Pathogenic:3
P3H1: PVS1, PM2, PM3 -
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) -
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Osteogenesis imperfecta Pathogenic:1
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P3H1-related disorder Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at