3-189995368-C-A

Variant names:

Variant summary

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

The NM_018192.4(P3H2):c.555G>T(p.Gln185His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,614,062 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 5 hom. )

Consequence

P3H2
NM_018192.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0850

Publications

9 publications found

Variant links:

Genes affected

P3H2 (HGNC:19317): (prolyl 3-hydroxylase 2) This gene encodes a member of the prolyl 3-hydroxylase subfamily of 2-oxo-glutarate-dependent dioxygenases. These enzymes play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. Mutations in this gene are associated with nonsyndromic severe myopia with cataract and vitreoretinal degeneration, and downregulation of this gene may play a role in breast cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

P3H2 Gene-Disease associations (from GenCC):

myopia, high, with cataract and vitreoretinal degeneration
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

P3H2 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=0.00795579).

BP6

Variant 3-189995368-C-A is Benign according to our data. Variant chr3-189995368-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547920.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000802 (122/152214) while in subpopulation SAS AF = 0.00932 (45/4828). AF 95% confidence interval is 0.00716. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4 link	c.555G>T	p.Gln185His	missense_variant	Exon 2 of 15	ENST00000319332.10	NP_060662.2	Q8IVL5-1
P3H2	NM_001134418.2 link	c.12G>T	p.Gln4His	missense_variant	Exon 2 of 15		NP_001127890.1	Q8IVL5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
P3H2	ENST00000319332.10 link	c.555G>T	p.Gln185His	missense_variant	Exon 2 of 15	1	NM_018192.4	ENSP00000316881.5	Q8IVL5-1
P3H2	ENST00000427335.6 link	c.12G>T	p.Gln4His	missense_variant	Exon 2 of 15	1		ENSP00000408947.2	Q8IVL5-2
P3H2	ENST00000444866.5 link	c.12G>T	p.Gln4His	missense_variant	Exon 2 of 4	4		ENSP00000391374.1	C9J313
P3H2	ENST00000426003.1 link	c.12G>T	p.Gln4His	missense_variant	Exon 2 of 4	4		ENSP00000394326.1	C9JSL4

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00121

AC:

303

AN:

251338

AF XY:

0.00149

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000660

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000851

AC:

1244

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000991

AC XY:

721

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000648

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00287

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00623

AC:

537

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000421

AC:

468

AN:

1111984

Other (OTH)

AF:

0.00147

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

139

209

278

348

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:

0.000802

AC:

122

AN:

152214

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41528

American (AMR)

AF:

0.000916

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00932

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68026

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000717

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00123

AC:

150

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myopia, high, with cataract and vitreoretinal degeneration

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 10, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.93

D;T;T;T

MetaRNN

Benign

0.0080

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

-0.085

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Uncertain

0.029

D;D;.;.

Polyphen

0.99

D;.;.;.

Vest4

0.41

MutPred

0.36

Gain of disorder (P = 0.1474);.;.;.;

MVP

0.32

MPC

0.28

ClinPred

0.055

GERP RS

2.4

Varity_R

0.083

gMVP

0.53

Mutation Taster

=89/11

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