Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000296388.10(P3H1):c.1930C>A(p.Gln644Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,611,248 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q644P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 56 hom. )

Consequence

P3H1
ENST00000296388.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.02

Publications

6 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=0.008805096).

BP6

Variant 1-42747397-G-T is Benign according to our data. Variant chr1-42747397-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468979.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0032 (488/152292) while in subpopulation EAS AF = 0.00521 (27/5184). AF 95% confidence interval is 0.00368. There are 7 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000296388.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
P3H1	NM_022356.4	MANE Select	c.1930C>A	p.Gln644Lys	missense	Exon 14 of 15	NP_071751.3
P3H1	NM_001243246.2		c.1930C>A	p.Gln644Lys	missense	Exon 14 of 14	NP_001230175.1
P3H1	NM_001146289.2		c.1930C>A	p.Gln644Lys	missense	Exon 14 of 15	NP_001139761.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
P3H1	ENST00000296388.10	TSL:1 MANE Select	c.1930C>A	p.Gln644Lys	missense	Exon 14 of 15	ENSP00000296388.5
P3H1	ENST00000397054.7	TSL:1	c.1930C>A	p.Gln644Lys	missense	Exon 14 of 15	ENSP00000380245.3
P3H1	ENST00000236040.8	TSL:2	c.1930C>A	p.Gln644Lys	missense	Exon 14 of 14	ENSP00000236040.4

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

488

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0327

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00483

AC:

1192

AN:

246944

AF XY:

0.00470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000206

Gnomad EAS exome

AF:

0.00371

Gnomad FIN exome

AF:

0.0372

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00977

GnomAD4 exome

AF:

0.00247

AC:

3606

AN:

1458956

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1774

AN XY:

725586

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.0000449

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.0000771

AC:

AN:

25934

East Asian (EAS)

AF:

0.0142

AC:

565

AN:

39660

South Asian (SAS)

AF:

0.000675

AC:

AN:

85910

European-Finnish (FIN)

AF:

0.0383

AC:

2012

AN:

52474

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000702

AC:

780

AN:

1110920

Other (OTH)

AF:

0.00305

AC:

184

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

207

414

622

829

1036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00320

AC:

488

AN:

152292

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41576

American (AMR)

AF:

0.000392

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00521

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0327

AC:

347

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68012

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00117

Hom.:

Bravo

AF:

0.000722

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000469

AC:

ExAC

AF:

0.00470

AC:

569

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000534

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Osteogenesis imperfecta type 8 (2)

not provided (1)

Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.053

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.073

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

PhyloP100

3.0

PrimateAI

Benign

0.42

PROVEAN

Benign

0.84

REVEL

Benign

0.065

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.14

Vest4

0.17

MVP

0.40

MPC

0.25

ClinPred

0.064

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.55

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over