rs55716016

Positions:

• chr1-42766833-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000296388.10(P3H1):​c.139G>T​(p.Ala47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 1,604,686 control chromosomes in the GnomAD database, including 1,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.041 (193 hom., cov: 33)
  • Exomes 𝑓: 0.032 (883 hom.)
• Consequence: P3H1 ENST00000296388.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.206

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025526285).
• BP6: Variant 1-42766833-C-A is Benign according to our data. Variant chr1-42766833-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 379443.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr1-42766833-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P3H1	NM_022356.4	c.139G>T	p.Ala47Ser	missense_variant	1/15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10	c.139G>T	p.Ala47Ser	missense_variant	1/15	1	NM_022356.4	ENSP00000296388	P1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6297 AN: 152182 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0521

GnomAD3 exomes AF: 0.0311 AC: 7174 AN: 230808 Hom.: 154 AF XY: 0.0320 AC XY: 4075 AN XY: 127536

Gnomad AFR exome AF: 0.0806

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00181

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.0318 AC: 46129 AN: 1452386 Hom.: 883 Cov.: 32 AF XY: 0.0320 AC XY: 23119 AN XY: 722992

Gnomad4 AFR exome AF: 0.0836

Gnomad4 AMR exome AF: 0.0234

Gnomad4 ASJ exome AF: 0.0391

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.0442

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0310

Gnomad4 OTH exome AF: 0.0319

GnomAD4 genome AF: 0.0414 AC: 6309 AN: 152300 Hom.: 193 Cov.: 33 AF XY: 0.0408 AC XY: 3035 AN XY: 74478

Gnomad4 AFR AF: 0.0757

Gnomad4 AMR AF: 0.0249

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0296

Gnomad4 OTH AF: 0.0510

Alfa AF: 0.0292 Hom.: 107

Bravo AF: 0.0432

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.0676 AC: 276

ESP6500EA AF: 0.0297 AC: 243

ExAC AF: 0.0306 AC: 3643

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0339

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta type 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Osteogenesis Imperfecta, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.064	.;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Benign	0.014
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.38	T;T;T;.
Polyphen		0.047, 0.0080	.;B;B;B
Vest4		0.090
MPC		0.94
ClinPred		0.019	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.052
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs55716016; hg19: chr1-43232504;