rs761389160

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022356.4(P3H1):c.326T>G(p.Phe109Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,577,294 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F109F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.42

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4 link	c.326T>G	p.Phe109Cys	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.326T>G	p.Phe109Cys	missense_variant	Exon 1 of 15	1	NM_022356.4	ENSP00000296388.5		Q32P28-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000338

AC:

AN:

177500

AF XY:

0.0000615

show subpopulations

Gnomad AFR exome

AF:

0.000118

Gnomad AMR exome

AF:

0.0000720

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000413

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1425104

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

705452

show subpopulations

African (AFR)

AF:

0.0000617

AC:

AN:

32412

American (AMR)

AF:

0.0000505

AC:

AN:

39626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25332

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37754

South Asian (SAS)

AF:

0.0000488

AC:

AN:

81998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49564

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.0000174

AC:

AN:

1093912

Other (OTH)

AF:

0.00

AC:

AN:

58888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000435

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000178

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 8

Uncertain:1

Apr 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 109 of the P3H1 protein (p.Phe109Cys). This variant is present in population databases (rs761389160, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with P3H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 468982). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.0064

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

.;.;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.9

M;M;M;.

PhyloP100

3.4

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;D;D;T

Sift4G

Uncertain

0.0060

D;D;D;.

Polyphen

1.0

.;D;D;D

Vest4

0.78

MutPred

0.27

Loss of stability (P = 0.0283);Loss of stability (P = 0.0283);Loss of stability (P = 0.0283);Loss of stability (P = 0.0283);

MVP

0.51

MPC

2.5

ClinPred

0.91

GERP RS

4.1

PromoterAI

0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.74

Mutation Taster

=63/37

polymorphism

(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