Genetic Variant P3H1:p.Pro718Thr (chr1-42746756-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022356.4(P3H1):c.2152C>A(p.Pro718Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,403,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P718A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

P3H1
NM_022356.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.717

Publications

2 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.072092235).

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
P3H1	NM_022356.4	MANE Select	c.2152C>A	p.Pro718Thr	missense	Exon 15 of 15	NP_071751.3
P3H1	NM_001243246.2		c.*156C>A		3_prime_UTR	Exon 14 of 14	NP_001230175.1
P3H1	NM_001146289.2		c.*77C>A		3_prime_UTR	Exon 15 of 15	NP_001139761.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
P3H1	ENST00000296388.10	TSL:1 MANE Select	c.2152C>A	p.Pro718Thr	missense	Exon 15 of 15	ENSP00000296388.5
P3H1	ENST00000397054.7	TSL:1	c.*77C>A		3_prime_UTR	Exon 15 of 15	ENSP00000380245.3
P3H1	ENST00000460031.5	TSL:5	n.2344C>A		non_coding_transcript_exon	Exon 14 of 14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1403220

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

692516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31732

American (AMR)

AF:

0.00

AC:

AN:

35924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25212

East Asian (EAS)

AF:

0.00

AC:

AN:

35952

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081106

Other (OTH)

AF:

0.00

AC:

AN:

58240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.3

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.13

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.50

M_CAP

Benign

0.0044

MetaRNN

Benign

0.072

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.72

PROVEAN

Benign

-0.96

REVEL

Benign

0.034

Sift

Benign

0.079

Sift4G

Benign

0.68

Polyphen

0.22

Vest4

0.097

MutPred

0.081

Gain of phosphorylation at P718 (P = 0.0163)

MVP

0.26

ClinPred

0.10

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over