chr1-42757902-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022356.4(P3H1):c.961G>A(p.Val321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V321V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051348776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4 link	c.961G>A	p.Val321Ile	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.961G>A	p.Val321Ile	missense_variant	Exon 5 of 15	1	NM_022356.4	ENSP00000296388.5		Q32P28-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 8

Uncertain:1

Jun 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals with a P3H1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on P3H1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 321 of the P3H1 protein (p.Val321Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.6

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.069

.;.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

N;N;N

PhyloP100

1.7

PrimateAI

Benign

0.27

PROVEAN

Benign

0.32

N;N;N

REVEL

Benign

0.024

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020, 0.0

.;B;B

Vest4

0.080

MutPred

0.36

Gain of ubiquitination at K325 (P = 0.1047);Gain of ubiquitination at K325 (P = 0.1047);Gain of ubiquitination at K325 (P = 0.1047);

MVP

0.19

MPC

0.15

ClinPred

0.43

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.16

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over