1-42746710-T-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_022356.4(P3H1):​c.2198A>G​(p.Lys733Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,551,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000091 ( 1 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

1
17

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.110

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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0063889027).
BP6
Variant 1-42746710-T-C is Benign according to our data. Variant chr1-42746710-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 727990.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
P3H1NM_022356.4 linkc.2198A>G p.Lys733Arg 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.2198A>G p.Lys733Arg missense_variant Exon 15 of 15 1 NM_022356.4 ENSP00000296388.5 Q32P28-1

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000263
AC:
41
AN:
155822
AF XY:
0.000242
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00250
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000228
GnomAD4 exome
AF:
0.0000908
AC:
127
AN:
1399416
Hom.:
1
Cov.:
31
AF XY:
0.0000913
AC XY:
63
AN XY:
690236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31600
American (AMR)
AF:
0.00
AC:
0
AN:
35706
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25182
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35738
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79244
European-Finnish (FIN)
AF:
0.00240
AC:
118
AN:
49266
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5692
European-Non Finnish (NFE)
AF:
0.00000741
AC:
8
AN:
1078968
Other (OTH)
AF:
0.0000172
AC:
1
AN:
58020
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
8
16
23
31
39
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.000377
AC XY:
28
AN XY:
74360
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41460
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00282
AC:
30
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.523
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:
0.0000529
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000915
AC:
7

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 8 Benign:1
Feb 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.053
T
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.0075
T
MetaRNN
Benign
0.0064
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L
PhyloP100
-0.11
PROVEAN
Benign
-0.18
N
REVEL
Benign
0.011
Sift
Benign
0.052
T
Sift4G
Benign
0.27
T
Polyphen
0.0030
B
Vest4
0.068
MVP
0.31
ClinPred
0.024
T
GERP RS
0.045
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.057
Mutation Taster
=96/4
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: rs769986758; hg19: chr1-43212381; API