chr1-42746753-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022356.4(P3H1):​c.2155G>A​(p.Glu719Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,553,798 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -2.93

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01901722).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
P3H1NM_022356.4 linkc.2155G>A p.Glu719Lys missense_variant Exon 15 of 15 ENST00000296388.10 NP_071751.3 Q32P28-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
P3H1ENST00000296388.10 linkc.2155G>A p.Glu719Lys missense_variant Exon 15 of 15 1 NM_022356.4 ENSP00000296388.5 Q32P28-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152006
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000580
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
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:
0.0000561
AC:
9
AN:
160458
AF XY:
0.0000588
show subpopulations
Gnomad AFR exome
AF:
0.000484
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000263
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000159
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000756
AC:
106
AN:
1401674
Hom.:
0
Cov.:
31
AF XY:
0.0000853
AC XY:
59
AN XY:
691566
show subpopulations
African (AFR)
AF:
0.000505
AC:
16
AN:
31678
American (AMR)
AF:
0.0000558
AC:
2
AN:
35832
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25198
East Asian (EAS)
AF:
0.000139
AC:
5
AN:
35874
South Asian (SAS)
AF:
0.0000377
AC:
3
AN:
79524
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49480
Middle Eastern (MID)
AF:
0.000176
AC:
1
AN:
5698
European-Non Finnish (NFE)
AF:
0.0000713
AC:
77
AN:
1080238
Other (OTH)
AF:
0.0000344
AC:
2
AN:
58152
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.456
Heterozygous variant carriers
0
6
11
17
22
28
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.000197
AC:
30
AN:
152124
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.000578
AC:
24
AN:
41490
American (AMR)
AF:
0.000196
AC:
3
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
67974
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000456
Hom.:
0
Bravo
AF:
0.000178
ESP6500AA
AF:
0.000723
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000371
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 8 Uncertain:2
Aug 26, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamic acid with lysine at codon 719 of the P3H1 protein (p.Glu719Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs372407655, ExAC 0.09%). 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: 536810). 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 lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Apr 11, 2023
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Osteogenesis imperfecta Uncertain:1
Apr 01, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Uncertain:1
Nov 28, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2155G>A (p.E719K) alteration is located in exon 15 (coding exon 15) of the P3H1 gene. This alteration results from a G to A substitution at nucleotide position 2155, causing the glutamic acid (E) at amino acid position 719 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
0.051
DANN
Benign
0.40
DEOGEN2
Benign
0.091
T
Eigen
Benign
-1.9
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.019
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.69
N
PhyloP100
-2.9
PROVEAN
Benign
-0.85
N
REVEL
Benign
0.042
Sift
Benign
0.56
T
Sift4G
Benign
0.48
T
Polyphen
0.0
B
Vest4
0.067
MVP
0.099
ClinPred
0.0078
T
GERP RS
-10
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.045
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs372407655; hg19: chr1-43212424; COSMIC: COSV52533577; COSMIC: COSV52533577; API