rs6700677

Positions:

chr1-42757818-C-T

Variant summary

Our verdict is Benign. Variant got -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).

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

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 -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 id is 379444.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr1-42757818-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
P3H1	NM_022356.4 linkuse as main transcript	c.1045G>A	p.Gly349Arg	missense_variant	5/15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10 linkuse as main transcript	c.1045G>A	p.Gly349Arg	missense_variant	5/15	1	NM_022356.4	ENSP00000296388	P1	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

GnomAD3 exomes

AF:

0.0438

AC:

11010

AN:

251490

Hom.:

304

AF XY:

0.0442

AC XY:

6003

AN XY:

135916

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 SAS exome

AF:

0.0551

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

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.0399

Gnomad4 ASJ exome

AF:

0.0612

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.0547

Gnomad4 FIN exome

AF:

0.0277

Gnomad4 NFE exome

AF:

0.0414

Gnomad4 OTH exome

AF:

0.0471

GnomAD4 genome

AF:

0.0586

AC:

8930

AN:

152290

Hom.:

361

Cov.:

AF XY:

0.0577

AC XY:

4299

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.0467

Gnomad4 ASJ

AF:

0.0605

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0557

Gnomad4 FIN

AF:

0.0310

Gnomad4 NFE

AF:

0.0407

Gnomad4 OTH

AF:

0.0681

Alfa

AF:

0.0470

Hom.:

475

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, 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. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2016

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

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

MutationTaster

Benign

1.0

D;D;D

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

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

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