rs573577299

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_022356.4(P3H1):c.2147G>C(p.Gly716Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,556,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. G716R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -1.58

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: 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004278332).

BP6

Variant 1-42746761-C-G is Benign according to our data. Variant chr1-42746761-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468981.

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.2147G>C	p.Gly716Ala	missense	Exon 15 of 15	NP_071751.3
P3H1	NM_001243246.2		c.*151G>C		3_prime_UTR	Exon 14 of 14	NP_001230175.1	Q32P28-3
P3H1	NM_001146289.2		c.*72G>C		3_prime_UTR	Exon 15 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.2147G>C	p.Gly716Ala	missense	Exon 15 of 15	ENSP00000296388.5	Q32P28-1
P3H1	ENST00000397054.7	TSL:1	c.*72G>C		3_prime_UTR	Exon 15 of 15	ENSP00000380245.3	Q32P28-4
P3H1	ENST00000907902.1		c.2471G>C	p.Gly824Ala	missense	Exon 15 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000159

AC:

AN:

163752

AF XY:

0.000138

show subpopulations

Gnomad AFR exome

AF:

0.00236

Gnomad AMR exome

AF:

0.000239

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000662

AC:

AN:

1404322

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

693212

show subpopulations

African (AFR)

AF:

0.00211

AC:

AN:

31788

American (AMR)

AF:

0.000361

AC:

AN:

35972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.00

AC:

AN:

36012

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000277

AC:

AN:

1081826

Other (OTH)

AF:

0.000154

AC:

AN:

58296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000637

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41546

American (AMR)

AF:

0.000262

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000416

Hom.:

Bravo

AF:

0.000695

ExAC

AF:

0.000179

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Osteogenesis imperfecta type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0090

(source)

DANN

Benign

0.099

DEOGEN2

Benign

0.077

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.39

M_CAP

Benign

0.0065

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-1.6

PROVEAN

Benign

-0.26

REVEL

Benign

0.0090

Sift

Benign

0.45

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.11

MVP

0.095

ClinPred

0.0010

GERP RS

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.032

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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