dbSNP rs113593896: P3H1:p.Asp441Gly (chr1-42754892-T-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_022356.4(P3H1):c.1322A>G(p.Asp441Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,614,182 control chromosomes in the GnomAD database, including 15 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 0.0033 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 11 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 7.44

Publications

11 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: G2P, Labcorp Genetics (formerly Invitae)
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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_022356.4

BP4

Computational evidence support a benign effect (MetaRNN=0.01019302).

BP6

Variant 1-42754892-T-C is Benign according to our data. Variant chr1-42754892-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283522.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0033 (502/152300) while in subpopulation NFE AF = 0.00573 (390/68014). AF 95% confidence interval is 0.00526. There are 4 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022356.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P3H1	NM_022356.4	MANE Select	c.1322A>G	p.Asp441Gly	missense	Exon 8 of 15	NP_071751.3
P3H1	NM_001243246.2		c.1322A>G	p.Asp441Gly	missense	Exon 8 of 14	NP_001230175.1	Q32P28-3
P3H1	NM_001146289.2		c.1322A>G	p.Asp441Gly	missense	Exon 8 of 15	NP_001139761.1	Q32P28-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P3H1	ENST00000296388.10	TSL:1 MANE Select	c.1322A>G	p.Asp441Gly	missense	Exon 8 of 15	ENSP00000296388.5	Q32P28-1
P3H1	ENST00000397054.7	TSL:1	c.1322A>G	p.Asp441Gly	missense	Exon 8 of 15	ENSP00000380245.3	Q32P28-4
P3H1	ENST00000907902.1		c.1646A>G	p.Asp549Gly	missense	Exon 8 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

502

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00395

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00573

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00258

AC:

648

AN:

251472

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00374

Gnomad NFE exome

AF:

0.00411

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00372

AC:

5436

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

2643

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.000805

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86258

European-Finnish (FIN)

AF:

0.00416

AC:

222

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00435

AC:

4834

AN:

1112004

Other (OTH)

AF:

0.00348

AC:

210

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

335

670

1004

1339

1674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<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:

0.00330

AC:

502

AN:

152300

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41560

American (AMR)

AF:

0.00124

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00395

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00573

AC:

390

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

114

143

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:

0.00402

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00332

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Osteogenesis imperfecta type 8 (3)

not specified (1)

Osteogenesis imperfecta (1)

P3H1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.044

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.3

PhyloP100

7.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.31

Sift

Uncertain

0.013

Sift4G

Benign

0.092

Polyphen

0.99

Vest4

0.60

MVP

0.68

MPC

0.83

ClinPred

0.013

GERP RS

5.6

Varity_R

0.19

gMVP

0.70

Mutation Taster

=92/8

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

Computational scores

Splicing

Publications

Other links and lift over