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rs149894086

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_022356.4(P3H1):c.1529A>G(p.Asn510Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,614,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N510T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.257
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007150173).
BP6
Variant 1-42752314-T-C is Benign according to our data. Variant chr1-42752314-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289042.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000893 (136/152266) while in subpopulation AFR AF= 0.00325 (135/41542). AF 95% confidence interval is 0.0028. There are 1 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
P3H1NM_022356.4 linkuse as main transcriptc.1529A>G p.Asn510Ser missense_variant 10/15 ENST00000296388.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
P3H1ENST00000296388.10 linkuse as main transcriptc.1529A>G p.Asn510Ser missense_variant 10/151 NM_022356.4 P1Q32P28-1

Frequencies

GnomAD3 genomes
AF:
0.000894
AC:
136
AN:
152148
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00326
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000251
AC:
63
AN:
251472
Hom.:
0
AF XY:
0.000191
AC XY:
26
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00314
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000958
AC:
140
AN:
1461842
Hom.:
1
Cov.:
32
AF XY:
0.0000866
AC XY:
63
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00308
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000893
AC:
136
AN:
152266
Hom.:
1
Cov.:
32
AF XY:
0.000859
AC XY:
64
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00325
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000881
Hom.:
0
Bravo
AF:
0.000918
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000329
AC:
40
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 24, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 12, 2017- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 24, 2016- -
P3H1-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 20, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Osteogenesis imperfecta type 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.048
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.64
Cadd
Benign
8.3
Dann
Benign
0.93
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.82
T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.0072
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.29
N;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-2.1
N;N;N
REVEL
Benign
0.023
Sift
Benign
0.28
T;T;T
Sift4G
Benign
0.46
T;T;T
Polyphen
0.0030, 0.0
.;B;B
Vest4
0.053
MVP
0.17
MPC
0.15
ClinPred
0.0023
T
GERP RS
-3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.028
gMVP
0.21

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs149894086; hg19: chr1-43217985; API