rs115108794

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_022356.4(P3H1):c.1501C>T(p.Arg501Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000413 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R501Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.71

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]

P3H1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018301934).

BP6

Variant 1-42752342-G-A is Benign according to our data. Variant chr1-42752342-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536818.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00185 (281/152260) while in subpopulation AFR AF= 0.00643 (267/41538). AF 95% confidence interval is 0.00579. There are 0 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H1	NM_022356.4 linkuse as main transcript	c.1501C>T	p.Arg501Trp	missense_variant	10/15	ENST00000296388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H1	ENST00000296388.10 linkuse as main transcript	c.1501C>T	p.Arg501Trp	missense_variant	10/15	1	NM_022356.4	P1	Q32P28-1

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00645

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000569

AC:

143

AN:

251440

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000264

AC:

386

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00693

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00185

AC:

281

AN:

152260

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00643

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000475

Hom.:

Bravo

AF:

0.00225

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 8

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Osteogenesis Imperfecta, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

P3H1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2020

This variant is associated with the following publications: (PMID: 26634552) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.0

M;M;M

MutationTaster

Benign

0.93

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.84

MVP

0.72

MPC

0.75

ClinPred

0.14

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.73

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over