rs72659348
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_022356.4(P3H1):c.747delC(p.Tyr250MetfsTer87) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
P3H1
NM_022356.4 frameshift
NM_022356.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.02
Publications
1 publications found
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]
P3H1 Gene-Disease associations (from GenCC):
- osteogenesis imperfecta type 8Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- osteogenesis imperfecta type 2Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- osteogenesis imperfecta type 3Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 1-42759261-AG-A is Pathogenic according to our data. Variant chr1-42759261-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1255.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_022356.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| P3H1 | MANE Select | c.747delC | p.Tyr250MetfsTer87 | frameshift | Exon 3 of 15 | NP_071751.3 | |||
| P3H1 | c.747delC | p.Tyr250MetfsTer87 | frameshift | Exon 3 of 14 | NP_001230175.1 | Q32P28-3 | |||
| P3H1 | c.747delC | p.Tyr250MetfsTer87 | frameshift | Exon 3 of 15 | NP_001139761.1 | Q32P28-4 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| P3H1 | TSL:1 MANE Select | c.747delC | p.Tyr250MetfsTer87 | frameshift | Exon 3 of 15 | ENSP00000296388.5 | Q32P28-1 | ||
| P3H1 | TSL:1 | c.747delC | p.Tyr250MetfsTer87 | frameshift | Exon 3 of 15 | ENSP00000380245.3 | Q32P28-4 | ||
| P3H1 | c.1071delC | p.Tyr358MetfsTer87 | frameshift | Exon 3 of 15 | ENSP00000577961.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152180
Hom.:
Cov.:
32
Gnomad AFR
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GnomAD2 exomes AF: 0.00000795 AC: 2AN: 251476 AF XY: 0.0000147 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251476
AF XY:
Gnomad AFR exome
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461890
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727246
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1112008
Other (OTH)
AF:
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
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2
0.00
0.20
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0.95
Allele balance
GnomAD4 genome 0.00000657 AC: 1AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74460 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152298
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74460
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41576
American (AMR)
AF:
AC:
0
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5182
South Asian (SAS)
AF:
AC:
0
AN:
4814
European-Finnish (FIN)
AF:
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68026
Other (OTH)
AF:
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
EpiCase
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EpiControl
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ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
2
-
-
Osteogenesis imperfecta type 8 (2)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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