rs6700677

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.1045G>A(p.Gly349Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,614,128 control chromosomes in the GnomAD database, including 1,950 homozygotes. In-silico tool predicts 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. G349G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 361 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1589 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.57

Publications

31 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=0.0021423697).

BP6

Variant 1-42757818-C-T is Benign according to our data. Variant chr1-42757818-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379444.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4 link	c.1045G>A	p.Gly349Arg	missense_variant	Exon 5 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.1045G>A	p.Gly349Arg	missense_variant	Exon 5 of 15	1	NM_022356.4	ENSP00000296388.5		Q32P28-1

Frequencies

GnomAD3 genomes

AF:

0.0586

AC:

8914

AN:

152172

Hom.:

359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.0605

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0557

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.0688

GnomAD2 exomes

AF:

0.0438

AC:

11010

AN:

251490

AF XY:

0.0442

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.0366

Gnomad ASJ exome

AF:

0.0607

Gnomad EAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0416

Gnomad OTH exome

AF:

0.0489

GnomAD4 exome

AF:

0.0430

AC:

62829

AN:

1461838

Hom.:

1589

Cov.:

AF XY:

0.0433

AC XY:

31456

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.115

AC:

3850

AN:

33474

American (AMR)

AF:

0.0399

AC:

1783

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0612

AC:

1599

AN:

26136

East Asian (EAS)

AF:

0.000680

AC:

AN:

39700

South Asian (SAS)

AF:

0.0547

AC:

4719

AN:

86254

European-Finnish (FIN)

AF:

0.0277

AC:

1480

AN:

53420

Middle Eastern (MID)

AF:

0.0758

AC:

437

AN:

5768

European-Non Finnish (NFE)

AF:

0.0414

AC:

46091

AN:

1111970

Other (OTH)

AF:

0.0471

AC:

2843

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3617

7234

10850

14467

18084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1776

3552

5328

7104

8880

<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:

0.0586

AC:

8930

AN:

152290

Hom.:

361

Cov.:

AF XY:

0.0577

AC XY:

4299

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.106

AC:

4396

AN:

41532

American (AMR)

AF:

0.0467

AC:

714

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

210

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5186

South Asian (SAS)

AF:

0.0557

AC:

269

AN:

4828

European-Finnish (FIN)

AF:

0.0310

AC:

329

AN:

10624

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0407

AC:

2766

AN:

68024

Other (OTH)

AF:

0.0681

AC:

144

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

427

855

1282

1710

2137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0478

Hom.:

890

Bravo

AF:

0.0632

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0449

AC:

173

ESP6500AA

AF:

0.108

AC:

478

ESP6500EA

AF:

0.0435

AC:

374

ExAC

AF:

0.0448

AC:

5442

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0493

EpiControl

AF:

0.0466

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:4

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

.;.;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.2

M;M;M

PhyloP100

7.6

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.47

MutPred

0.31

Gain of methylation at G349 (P = 0.1357);Gain of methylation at G349 (P = 0.1357);Gain of methylation at G349 (P = 0.1357);

MPC

0.80

ClinPred

0.041

GERP RS

5.8

Varity_R

0.57

gMVP

0.68

Mutation Taster

=69/31

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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