rs55716016

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_022356.4(P3H1):c.139G>T(p.Ala47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 1,604,686 control chromosomes in the GnomAD database, including 1,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A47A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.041 ( 193 hom., cov: 33)

Exomes 𝑓: 0.032 ( 883 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.206

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
osteogenesis imperfecta type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

P3H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025526285).

BP6

Variant 1-42766833-C-A is Benign according to our data. Variant chr1-42766833-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379443.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4 link	c.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 15	ENST00000296388.10	NP_071751.3	Q32P28-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10 link	c.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 15	1	NM_022356.4	ENSP00000296388.5		Q32P28-1

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6297

AN:

152182

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0756

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.0249

Gnomad ASJ

AF:

0.0389

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0437

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0296

Gnomad OTH

AF:

0.0521

GnomAD2 exomes

AF:

0.0311

AC:

7174

AN:

230808

AF XY:

0.0320

show subpopulations

Gnomad AFR exome

AF:

0.0806

Gnomad AMR exome

AF:

0.0216

Gnomad ASJ exome

AF:

0.0392

Gnomad EAS exome

AF:

0.00181

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0320

GnomAD4 exome

AF:

0.0318

AC:

46129

AN:

1452386

Hom.:

883

Cov.:

AF XY:

0.0320

AC XY:

23119

AN XY:

722992

show subpopulations

African (AFR)

AF:

0.0836

AC:

2796

AN:

33464

American (AMR)

AF:

0.0234

AC:

1045

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0391

AC:

1021

AN:

26098

East Asian (EAS)

AF:

0.000781

AC:

AN:

39684

South Asian (SAS)

AF:

0.0442

AC:

3811

AN:

86244

European-Finnish (FIN)

AF:

0.0178

AC:

792

AN:

44430

Middle Eastern (MID)

AF:

0.0411

AC:

237

AN:

5768

European-Non Finnish (NFE)

AF:

0.0310

AC:

34471

AN:

1111718

Other (OTH)

AF:

0.0319

AC:

1925

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3124

6249

9373

12498

15622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1346

2692

4038

5384

6730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0414

AC:

6309

AN:

152300

Hom.:

193

Cov.:

AF XY:

0.0408

AC XY:

3035

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0757

AC:

3146

AN:

41570

American (AMR)

AF:

0.0249

AC:

381

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

135

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5176

South Asian (SAS)

AF:

0.0439

AC:

212

AN:

4828

European-Finnish (FIN)

AF:

0.0210

AC:

223

AN:

10616

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0296

AC:

2010

AN:

68012

Other (OTH)

AF:

0.0510

AC:

108

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

312

623

935

1246

1558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0319

Hom.:

292

Bravo

AF:

0.0432

TwinsUK

AF:

0.0310

AC:

115

ALSPAC

AF:

0.0358

AC:

138

ESP6500AA

AF:

0.0676

AC:

276

ESP6500EA

AF:

0.0297

AC:

243

ExAC

AF:

0.0306

AC:

3643

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0357

EpiControl

AF:

0.0339

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 8

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis Imperfecta, Recessive

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

May 06, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Osteogenesis imperfecta

Benign:1

Jul 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.064

.;.;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.57

T;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L;.

PhyloP100

0.21

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.34

N;N;N;N

REVEL

Benign

0.014

Sift

Benign

0.39

T;T;T;T

Sift4G

Benign

0.38

T;T;T;.

Polyphen

0.047, 0.0080

.;B;B;B

Vest4

0.090

MPC

0.94

ClinPred

0.019

GERP RS

3.2

PromoterAI

0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.052

gMVP

0.52

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over